EP0471515A1 - Ring-substituted 2-amino-1,2,3,4-tetra-hydronaphthalenes, 3-aminochromanes and 3-aminothiochromanes - Google Patents
Ring-substituted 2-amino-1,2,3,4-tetra-hydronaphthalenes, 3-aminochromanes and 3-aminothiochromanes Download PDFInfo
- Publication number
- EP0471515A1 EP0471515A1 EP91307328A EP91307328A EP0471515A1 EP 0471515 A1 EP0471515 A1 EP 0471515A1 EP 91307328 A EP91307328 A EP 91307328A EP 91307328 A EP91307328 A EP 91307328A EP 0471515 A1 EP0471515 A1 EP 0471515A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- alkyl
- compound
- aryl
- substituted
- hydrogen
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- LCGFVWKNXLRFIF-UHFFFAOYSA-N 1,2,3,4-tetrahydronaphthalen-2-amine Chemical class C1=CC=C2CC(N)CCC2=C1 LCGFVWKNXLRFIF-UHFFFAOYSA-N 0.000 title abstract description 10
- SVWDNDQOXZHBRM-UHFFFAOYSA-N 3,4-dihydro-2h-chromen-3-amine Chemical class C1=CC=C2CC(N)COC2=C1 SVWDNDQOXZHBRM-UHFFFAOYSA-N 0.000 title abstract description 6
- HMJPRXLPAGOYFX-UHFFFAOYSA-N 3,4-dihydro-2h-thiochromen-3-amine Chemical class C1=CC=C2CC(N)CSC2=C1 HMJPRXLPAGOYFX-UHFFFAOYSA-N 0.000 title abstract description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 104
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 61
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 34
- 239000001257 hydrogen Substances 0.000 claims abstract description 34
- 125000003118 aryl group Chemical group 0.000 claims abstract description 28
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 22
- 239000002253 acid Substances 0.000 claims abstract description 19
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 19
- 150000003839 salts Chemical class 0.000 claims abstract description 19
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims abstract description 18
- 125000003107 substituted aryl group Chemical group 0.000 claims abstract description 17
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 13
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims abstract description 13
- 125000002496 methyl group Chemical class [H]C([H])([H])* 0.000 claims abstract description 9
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims abstract description 7
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims abstract description 7
- 239000000556 agonist Substances 0.000 claims abstract description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 7
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 40
- 239000004480 active ingredient Substances 0.000 claims description 13
- 241000124008 Mammalia Species 0.000 claims description 7
- 230000009471 action Effects 0.000 claims description 5
- 239000003085 diluting agent Substances 0.000 claims description 5
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 3
- 230000003647 oxidation Effects 0.000 claims description 3
- 238000007254 oxidation reaction Methods 0.000 claims description 3
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000004104 aryloxy group Chemical group 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 5
- 102000017911 HTR1A Human genes 0.000 abstract description 4
- 150000003462 sulfoxides Chemical class 0.000 abstract description 3
- 150000003457 sulfones Chemical class 0.000 abstract description 2
- 101710138638 5-hydroxytryptamine receptor 1A Proteins 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 125
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 109
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 106
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 78
- 239000000203 mixture Substances 0.000 description 76
- -1 homopiperazinyl moiety Chemical group 0.000 description 51
- 229940073584 methylene chloride Drugs 0.000 description 41
- 238000006243 chemical reaction Methods 0.000 description 35
- 239000000243 solution Substances 0.000 description 34
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 31
- 239000000047 product Substances 0.000 description 27
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 25
- 235000011114 ammonium hydroxide Nutrition 0.000 description 25
- 239000000741 silica gel Substances 0.000 description 25
- 229910002027 silica gel Inorganic materials 0.000 description 25
- 238000000034 method Methods 0.000 description 23
- 239000000908 ammonium hydroxide Substances 0.000 description 20
- 239000003921 oil Substances 0.000 description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- 239000000284 extract Substances 0.000 description 18
- 239000000543 intermediate Substances 0.000 description 18
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 17
- 229910052938 sodium sulfate Inorganic materials 0.000 description 17
- 235000011152 sodium sulphate Nutrition 0.000 description 17
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 16
- MRVOVSJOIOFTKG-UHFFFAOYSA-N 8-bromo-n,n-dipropyl-1,2,3,4-tetrahydronaphthalen-2-amine Chemical compound C1=CC(Br)=C2CC(N(CCC)CCC)CCC2=C1 MRVOVSJOIOFTKG-UHFFFAOYSA-N 0.000 description 15
- 238000002360 preparation method Methods 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 239000000463 material Substances 0.000 description 13
- 238000000921 elemental analysis Methods 0.000 description 12
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 11
- 229940093499 ethyl acetate Drugs 0.000 description 11
- 235000019439 ethyl acetate Nutrition 0.000 description 11
- 239000000706 filtrate Substances 0.000 description 11
- 238000009472 formulation Methods 0.000 description 11
- 150000002431 hydrogen Chemical group 0.000 description 11
- 102000005962 receptors Human genes 0.000 description 11
- 108020003175 receptors Proteins 0.000 description 11
- 239000012458 free base Substances 0.000 description 10
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 9
- 239000007832 Na2SO4 Substances 0.000 description 8
- 230000027455 binding Effects 0.000 description 8
- 239000012043 crude product Substances 0.000 description 8
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 8
- 150000001412 amines Chemical class 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 239000002808 molecular sieve Substances 0.000 description 7
- 230000002829 reductive effect Effects 0.000 description 7
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- RWEVGLMABSFMKW-UHFFFAOYSA-N 8-bromo-3,4-dihydro-1h-naphthalen-2-one Chemical compound C1CC(=O)CC2=C1C=CC=C2Br RWEVGLMABSFMKW-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 6
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 6
- 150000002576 ketones Chemical class 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 150000003891 oxalate salts Chemical class 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 5
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 5
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 5
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 5
- 125000001246 bromo group Chemical group Br* 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 238000004587 chromatography analysis Methods 0.000 description 5
- 238000003776 cleavage reaction Methods 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 208000035475 disorder Diseases 0.000 description 5
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 5
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 5
- 239000004615 ingredient Substances 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 230000007017 scission Effects 0.000 description 5
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 5
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 4
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 4
- DQEZEDNXYWWKJS-UHFFFAOYSA-N 5-bromo-4h-chromen-3-one Chemical compound O1CC(=O)CC2=C1C=CC=C2Br DQEZEDNXYWWKJS-UHFFFAOYSA-N 0.000 description 4
- 102000040125 5-hydroxytryptamine receptor family Human genes 0.000 description 4
- 108091032151 5-hydroxytryptamine receptor family Proteins 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 208000019901 Anxiety disease Diseases 0.000 description 4
- IXQXUHRMNFLCQS-UHFFFAOYSA-N C1CCCC2=C1C=CC=C2[Li] Chemical compound C1CCCC2=C1C=CC=C2[Li] IXQXUHRMNFLCQS-UHFFFAOYSA-N 0.000 description 4
- 0 I*C1Cc2c(C3OC3)cccc2CC1 Chemical compound I*C1Cc2c(C3OC3)cccc2CC1 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- 230000036506 anxiety Effects 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
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- 125000004494 ethyl ester group Chemical group 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000007903 gelatin capsule Substances 0.000 description 4
- 125000005843 halogen group Chemical group 0.000 description 4
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- FKHIFSZMMVMEQY-UHFFFAOYSA-N talc Chemical compound [Mg+2].[O-][Si]([O-])=O FKHIFSZMMVMEQY-UHFFFAOYSA-N 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- 238000010626 work up procedure Methods 0.000 description 4
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 3
- ASXGJMSKWNBENU-UHFFFAOYSA-N 8-OH-DPAT Chemical compound C1=CC(O)=C2CC(N(CCC)CCC)CCC2=C1 ASXGJMSKWNBENU-UHFFFAOYSA-N 0.000 description 3
- YNXLDZYAFGPNHL-UHFFFAOYSA-N 8-bromo-1,2,3,4-tetrahydronaphthalen-2-amine Chemical compound C1=CC(Br)=C2CC(N)CCC2=C1 YNXLDZYAFGPNHL-UHFFFAOYSA-N 0.000 description 3
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- 230000002378 acidificating effect Effects 0.000 description 3
- 230000006399 behavior Effects 0.000 description 3
- ZTQSAGDEMFDKMZ-UHFFFAOYSA-N butyric aldehyde Natural products CCCC=O ZTQSAGDEMFDKMZ-UHFFFAOYSA-N 0.000 description 3
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 235000014632 disordered eating Nutrition 0.000 description 3
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- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 description 2
- RAEVOBPXEHVUFY-UHFFFAOYSA-N 1-(4-nitrophenyl)ethanamine Chemical compound CC(N)C1=CC=C([N+]([O-])=O)C=C1 RAEVOBPXEHVUFY-UHFFFAOYSA-N 0.000 description 2
- HUJSLWBEIXQTJY-UHFFFAOYSA-N 1-[7-(dipropylamino)-5,6,7,8-tetrahydronaphthalen-1-yl]-2,2,2-trifluoroethanone Chemical compound C1=CC(C(=O)C(F)(F)F)=C2CC(N(CCC)CCC)CCC2=C1 HUJSLWBEIXQTJY-UHFFFAOYSA-N 0.000 description 2
- RNNBTLNORQFREY-UHFFFAOYSA-N 1-[7-(dipropylamino)-5,6,7,8-tetrahydronaphthalen-1-yl]-2-methoxyethanone Chemical compound C1=CC(C(=O)COC)=C2CC(N(CCC)CCC)CCC2=C1 RNNBTLNORQFREY-UHFFFAOYSA-N 0.000 description 2
- YOBHPMBZYIAUKW-UHFFFAOYSA-N 1-[7-(dipropylamino)-5,6,7,8-tetrahydronaphthalen-1-yl]-2-methylpropan-1-one Chemical compound C1=CC(C(=O)C(C)C)=C2CC(N(CCC)CCC)CCC2=C1 YOBHPMBZYIAUKW-UHFFFAOYSA-N 0.000 description 2
- HQQPIPVDFCDLQI-UHFFFAOYSA-N 1-[7-(dipropylamino)-5,6,7,8-tetrahydronaphthalen-1-yl]-3-methylbutan-1-one Chemical compound C1=CC(C(=O)CC(C)C)=C2CC(N(CCC)CCC)CCC2=C1 HQQPIPVDFCDLQI-UHFFFAOYSA-N 0.000 description 2
- SDJCCUJEEKDIBV-UHFFFAOYSA-N 1-[7-(dipropylamino)-5,6,7,8-tetrahydronaphthalen-1-yl]ethanone Chemical compound C1=CC(C(C)=O)=C2CC(N(CCC)CCC)CCC2=C1 SDJCCUJEEKDIBV-UHFFFAOYSA-N 0.000 description 2
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- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 2
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- 239000005711 Benzoic acid Substances 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
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- 206010020772 Hypertension Diseases 0.000 description 2
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- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
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- LZFIOSVZIQOVFW-UHFFFAOYSA-N propyl 2-hydroxybenzoate Chemical class CCCOC(=O)C1=CC=CC=C1O LZFIOSVZIQOVFW-UHFFFAOYSA-N 0.000 description 1
- UORVCLMRJXCDCP-UHFFFAOYSA-M propynoate Chemical compound [O-]C(=O)C#C UORVCLMRJXCDCP-UHFFFAOYSA-M 0.000 description 1
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- 229940116351 sebacate Drugs 0.000 description 1
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- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 1
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- KXCAEQNNTZANTK-UHFFFAOYSA-N stannane Chemical compound [SnH4] KXCAEQNNTZANTK-UHFFFAOYSA-N 0.000 description 1
- 229910000080 stannane Inorganic materials 0.000 description 1
- 125000003638 stannyl group Chemical group [H][Sn]([H])([H])* 0.000 description 1
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- TYFQFVWCELRYAO-UHFFFAOYSA-L suberate(2-) Chemical compound [O-]C(=O)CCCCCCC([O-])=O TYFQFVWCELRYAO-UHFFFAOYSA-L 0.000 description 1
- 208000011117 substance-related disease Diseases 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
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- BBFIJKFOMYOWJU-UHFFFAOYSA-N tert-butyl 5-bromo-3-oxo-4h-chromene-4-carboxylate Chemical compound C1=CC(Br)=C2C(C(=O)OC(C)(C)C)C(=O)COC2=C1 BBFIJKFOMYOWJU-UHFFFAOYSA-N 0.000 description 1
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- YONPGGFAJWQGJC-UHFFFAOYSA-K titanium(iii) chloride Chemical compound Cl[Ti](Cl)Cl YONPGGFAJWQGJC-UHFFFAOYSA-K 0.000 description 1
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
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- 229940071104 xylenesulfonate Drugs 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C215/64—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with rings other than six-membered aromatic rings being part of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
- C07C225/20—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of the carbon skeleton
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
Definitions
- 5-HT receptors There are multiple types of 5-HT receptors. These receptors have been classified as 5-HT1, 5-HT2, and 5-HT3 receptors, with the former being further divided into the sub-classes 5-HT 1A , 5-HT 1B , 5-HT 1C , and 5-HT 1D .
- Co-pending application Serial No. 315,750 filed February 27, 1989 describes certain 2-aminotetralins substituted in the 8-position by formyl, cyano, halo, hydroxymethyl, carboxamido, carboxyl, or alkoxycarbonyl. The compounds are described as exhibiting high binding affinity at the 5-HT 1A receptor.
- 2-aminotetralins in which the 8-position is substituted by, among others, formyl are also described in EPO Patent Application No. 272,534.
- co-pending application Serial No. 315,752 filed February 27, 1989 describes other 2-aminotetralins substituted in the 8-position and 3-aminochromanes substituted in the 5-position by sulfides, sulfoxides, and sulfones. These compounds, as well, are described as having binding affinity at the 5-HT 1A receptor.
- 2-aminotetralins are described in European Patent Application No. 343,830, published November 29, 1989. These compounds have a piperazinyl or homopiperazinyl moiety in the 2-position and, distinct from the foregoing tetralins, do not exhibit affinity for serotonin receptors but rather inhibit the re-uptake of serotonin.
- 5-HT 1A agonist activity a further class of compounds which, by reason of their 5-HT 1A agonist activity, are useful in the treatment, for example, of sexual dysfunction, anxiety, depression, obsessive-compulsive behavior, cognition disorders, emesis, drug abuse, hypertension, excess acid secretion, and eating disorders, such as anorexia.
- the present invention provides novel ring-substituted 2-amino-1,2,3,4-tetrahydronaphthalenes and 3-aminochromanes which are selective agonists at the 5-HT 1A receptor.
- this invention is directed to a compound of the formula in which R is C1-C4 alkyl, C3-C4 alkenyl, or cyclopropylmethyl; R3 is hydrogen; or R and R3 taken together are a divalent group of the formula -CH2CH2CH2-; R1 is hydrogen, C1-C4 alkyl, C3-C4 alkenyl, cyclopropylmethyl, aryl(C1-C4-alkyl), -COR4, -(CH2) n S(C1-C4 alkyl) or -(CH2) n CONR5R6; n is an integer from 1 to 4; R4 is hydrogen, C1-C4 alkyl, C1-C4 alkoxy, or phenyl; R5 and R6 are independently hydrogen, a C1-C4 alkyl, or C3-C7 cycloalkyl with the proviso that when one of R5 or R6 is cycloalkyl the other is hydrogen
- This invention also provides a pharmaceutical formulation which comprises, in association with a pharmaceutically acceptable carrier, diluent, or excipient, a compound of the formula in which R is C1-C4 alkyl, C3-C4 alkenyl or cyclopropylmethyl; R3 is hydrogen; or R and R3 taken together are a divalent group of the formula -CH2CH2CH2-; R1 is hydrogen, C1-C4 alkyl, C3-C4 alkenyl, cyclopropylmethyl, aryl(C1-C4-alkyl), -COR4, -(CH2) n S(C1-C4 alkyl) or -(CH2) n CONR5R6; n is an integer from 1 to 4; R4 is hydrogen, C1-C4 alkyl, C1-C4 alkoxy, or phenyl; R5 and R6 are independently hydrogen, C1-C4 alkyl, or C3-C7 cycloalkyl with the pro
- a further embodiment of the invention is a method for effecting a biological response at the 5-HT 1A receptor. More particularly, further embodiments are methods for treating a variety of disorders in mammals which may be treated by stimulating 5-HT 1A receptors. Included among these disorders are anxiety, depression, sexual dysfunction, obsessive-compulsive behavior, hypertension, excess acid secretion, and eating disorders.
- R is C1-C4 alkyl, C3-C4 alkenyl or cyclopropylmethyl;
- R3 is hydrogen; or R and R3 taken together are a divalent group of the formula -CH2CH2CH2-;
- R1 is hydrogen, C1-C4 alkyl, C3-C4 alkenyl, cyclopropylmethyl, aryl(C1-C4-alkyl), -COR4, -(CH2) n S(C1-C4 alkyl) or -(CH2) n CONR5R6;
- n is an integer from 1 to 4;
- R4 is hydrogen, C1-C4 alkyl, C1-C4 alkoxy, or phenyl;
- R5 and R6 are independently hydrogen, C1-C4 alkyl, or C3-C7 cycloalkyl with the proviso that when one of R5 or R6 is cycloalkyl the other is hydrogen;
- X is -
- C1-C4 alkyl means a straight or branched alkyl chain having from one to four carbon atoms.
- Such C1-C4 alkyl groups are methyl, ethyl, n -propyl, isopropyl, n -butyl, isobutyl, sec -butyl, and t -butyl.
- C1-C8 alkyl means a straight or branched alkyl chain having from one to eight carbon atoms. Groups which are included in such term are methyl, ethyl, n -propyl, isopropyl, n -butyl, isobutyl, sec -butyl, t -butyl, n -pentyl, 2-methylbutyl, 3-methylbutyl, n -hexyl, 4-methylpentyl, n -heptyl, 3-ethylpentyl, 2-methylhexyl, 2,3-dimethylpentyl, n -octyl, 3-propylpentyl, 6-methylheptyl, and the like.
- C1-C4 alkoxy means any of methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, and sec-butoxy.
- aryl means an aromatic carbocyclic structure. Examples of such ring structures are phenyl, naphthyl, and the like.
- C3-C7 cycloalkyl means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
- aryl (C1-C4 alkyl) means an aromatic carbocyclic structure joined to a C1-C4 alkyl group. Examples of such groups are benzyl, phenylethyl, ⁇ -methylbenzyl, 3-phenylpropyl, ⁇ -naphthylmethyl, ⁇ -naphthylmethyl, 4-phenylbutyl, and the like.
- C2-C4 alkenyl means a straight or branched hydrocarbon chain having from two to four carbon atoms and containing one double bond.
- Groups which are included in such terms are vinyl, 1-methylvinyl, 2-methylvinyl, allyl, 2-butenyl, 3-butenyl, 1-butenyl, 1-methylallyl, 2-methylallyl, and the like.
- C3-C4 alkenyl is specifically defined to mean any of allyl, 2-butenyl, 3-butenyl, and 2-methylallyl.
- C1-C8 alkyl, the aryl, and the aryl (C1-C4 alkyl) groups may be substituted by one or two moieties.
- Typical aryl and/or alkyl substituents are C1-C3 alkoxy, halo, hydroxy, C1-C3 thioalkyl, and the like.
- the aryl and aryl (C1-C4 alkyl) groups may also be substituted by a C1-C3 alkyl or a trifluoromethyl group.
- C1-C3 alkyl means any of methyl, ethyl, n -propyl, and isopropyl
- C1-C3 alkoxy means any of methoxy, ethoxy, n-propoxy, and isopropoxy
- halo means any of fluoro, chloro, bromo, and iodo
- C1-C3 thioalkyl means any of methylthio, ethylthio, n -propylthio, and isopropylthio.
- substituted C1-C8 alkyl examples include methoxymethyl, trifluoromethyl, 6-chlorohexyl, 2-bromopropyl, 2-ethoxy-4-iodobutyl, 3-hydroxypentyl, methylthiomethyl, and the like.
- substituted aryl examples include p -bromophenyl, m -iodophenyl, p -tolyl, o -hydroxyphenyl, ⁇ -(4-hydroxy)naphthyl, p -(methylthio)phenyl, m -trifluoromethylphenyl, 2-chloro-4-methoxyphenyl, ⁇ -(5-chloro)naphthyl, and the like.
- substituted aryl C1-C4 alkyl
- substituted aryl C1-C4 alkyl
- p -chlorobenzyl o -methoxybenzyl
- m -(methylthio)- ⁇ -methylbenzyl 3-(4′-trifluoromethylphenyl)-propyl
- o -iodobenzyl p -methylbenzyl, and the like.
- R and R1 preferably are both C1-C4 alkyl, and, more preferably, both are n -propyl.
- X preferably is -CH2-.
- R2 preferably is C1-C8 alkyl, and, more preferably, C1-C5 alkyl. Most preferably, R2 is t -butyl.
- the compounds of the present invention possess an asymmetric carbon represented by the carbon atom labeled with an asterisk in the following formula: As such, each of the compounds exists as its individual d- and l-stereoisomers and also as the racemic mixture of such isomers. Accordingly, the compounds of the present invention include not only the dl-racemates but also their respective optically active d- and l-isomers.
- the invention includes pharmaceutically acceptable acid addition salts of the compounds defined by the above formula in which A is
- the compounds of this invention are amines, they are basic in nature and accordingly react with any of a number of inorganic and organic acids to form pharmaceutically acceptable acid addition salts. Since the free amines of the compounds of this invention are typically oils at room temperature, it is preferable to convert the free amines to their corresponding pharmaceutically acceptable acid addition salts for ease of handling and administration, since the latter are routinely solid at room temperature.
- Acids commonly employed to form such salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as maleic, fumaric, p -toluenesulfonic, methanesulfonic acid, oxalic acid, p -bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.
- inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like
- organic acids such as maleic, fumaric, p -toluenesulfonic, methanesulfonic acid, oxalic acid, p -bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.
- Examples of such pharmaceutically acceptable salts thus are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phen
- solvates may form solvates with water or organic solvents such as ethanol. Such solvates also are included as compounds of this invention.
- the compounds of the present invention may be prepared by procedures well known to those of ordinary skill in the art.
- the compounds in which X is -CH2- and R3 is hydrogen preferably are synthesized by preparation of an 8-bromo-2-tetralone.
- the 8-bromo-2-tetralone then is reductively aminated with the desired amine to produce the desired 2-amino-8-bromotetralin intermediate.
- the 8-bromo intermediate then is treated to produce the desired product directly or via the corresponding compound in which the group in the 8-position is R2CH(OH)-.
- the 8-bromo-2-tetralones represent intermediates which, when reductively aminated and treated, via lithiation, with the appropriate reagent, result in compounds of this invention.
- the reaction involves the use of an aldehyde
- tetralones are available by any of a wide range of recognized methods. For example, they can be produced by a Friedel-Crafts reaction of an appropriately ring-substituted phenylacetyl chloride with ethylene in the presence of aluminum chloride.
- the tetralone once formed, can, by simple reductive amination using the selected amine, be converted to a 2-amino-8-bromo-1,2,3,4-tetrahydronaphthalene useful as an intermediate to a compound of this invention.
- the tetralone is first reacted with the amine to form the corresponding enamine after which the enamine is reduced with sodium borohydride to the tetrahydronaphthalene.
- the 2-amino-8-bromo-1,2,3,4-tetrahydronaphthalene can be used to produce compounds of this invention by formation of a lithium intermediate via a lithiation reaction using an alkyllithium, preferably n -butyllithium.
- the reactive lithium intermediate then is treated with an appropriate carbonyl compound to produce either the ketone directly or a precursor of the ketone.
- treatment of the 8-lithio tetralin with a compound R2COZ, where Z is halo, alkoxy, hydroxy, aryloxy, -S-(C1-C3 alkyl),-OCO2R′, and the like, will, upon workup, yield the desired ketone.
- the aforementioned alcohol can also be prepared by addition of a suitable organo-metallic reagent (R2M in which M is Li, MgW, ZnW, and the like, W being an appropriate halide) to an 8-formyl-2-aminotetralin.
- R2M suitable organo-metallic reagent
- the 8-formyl-2-aminotetralin is prepared by addition of the 8-lithio-2-aminotetralin to dimethylformamide with aqueous workup of the resulting product.
- the 8-bromo-2-tetralone can first be protected and the bromo substituent converted to the appropriate ketone as described above.
- the resulting 8-acyl-2-tetralone, after deprotection, can then be reductively aminated to a compound of this invention.
- the 8-lithio tetralin may be replaced by the corresponding Grignard reagent to yield the desired product.
- the compounds of this invention in which X is oxygen are available by reductive amination and bromo replacement as in the foregoing, but using 5-bromo-3-chromanone.
- the latter can be produced by a sequence of reactions beginning with m -bromophenol. Briefly, m -bromophenol is treated with allyl bromide in the presence of potassium carbonate to produce allyl 3-bromophenyl ether. The ether is converted to 2-allyl-3-bromophenol upon heating it in the presence of N,N-dimethylaniline. The phenol, upon reaction with ethyl chloroacetate, is converted to the ethyl ester of 2-allyl-3-(carboxymethoxy)bromobenzene.
- the allyl group Upon oxidation using ozone followed by reductive work up, the allyl group is converted to a formylmethyl substituent which is then further oxidized using Jones' Reagent to the carboxymethyl substituent, the resulting product being the ethyl ester of (2-carboxymethyl-3-bromo)phenoxyacetic acid.
- the partial ester is converted to the diethyl ester using ethanol and gaseous hydrogen chloride.
- the diester In the presence of potassium t -butoxide, the diester is cyclized to a mixture of 4-ethoxycarbonyl-5-bromo-3-chromanone and 2-ethoxycarbonyl-5-bromo-3-chromanone. Upon heating in the presence of acid, the latter is converted to 5-bromo-3-chromanone.
- An alternate and improved synthesis of the 5-bromo-3-chromanone involves a sequence of reactions beginning with the ethyl ester of (2-allyl-3-carboxymethoxy)bromobenzene.
- the bromobenzene is oxidized using ozone to form, upon work-up with dimethyl thioether, the ethyl ester of (2-formylmethyl-3-carboxymethoxy)bromobenzene.
- the formylmethyl substituent is further oxidized to carboxymethyl using Jones' Reagent, the resulting product being (2-bromo-6-ethoxycarbonylmethoxy)phenylacetic acid.
- the acid is esterified to the t -butyl ester using t -butyl acetate and sulfuric acid, after which the resulting diester is cyclized in the presence of potassium t -butoxide to 4- t -butoxycarbonyl-5-bromo-3-chromanone.
- the t -butoxycarbonyl group then is cleaved using trifluoroacetic acid with formation of the desired 5-bromo-3-chromanone.
- the compounds of this invention in which X is sulfur are available by bromo replacement of the corresponding 2-amino-5-bromothiochromanes.
- the latter are available by a sequence of reactions beginning with m -bromothiophenol.
- the thiophenol is treated in base with ⁇ -chloropropionic acid to produce m -bromophenylthiopropionic acid.
- the acid then is cyclized with polyphosphoric acid or with thionyl chloride or phosgene and a Lewis acid to produce a mixture of 5-bromo-4-thiochromanone and 7-bromo-4-thiochromanone.
- the thiochromanone mixture is reduced using, for example, sodium borohydride, to produce 4-bromo-1,2-benzothiapyran which is then oxidized with an organic peroxide to the corresponding sulfoxide having an epoxy group in the 3,4 position.
- 5-bromo-3-thiochromanone sulfoxide is formed which can be reduced to the corresponding thiochromanone using dimethyl sulfide in the presence of trifluroacetic anhydride, oxalyl chloride, thionyl chloride, and the like, or reductively aminated to the 3-amino-5-bromothiochromane sulfoxide by treatment with the appropriate amine and sodium borohydride. The latter is reduced to the desired 3-amino-5-bromothiochromane using trifluoroacetic anhydride.
- reaction proceeds via a trialkylstannyl intermediate of the formula in which R7 is C1-C4 alkyl.
- the stannyl intermediate then is reacted with an acyl chloride in the presence of a suitable catalyst such as dichlorobis(triphenylphosphine)palladium II or palladium dichloride.
- a suitable catalyst such as dichlorobis(triphenylphosphine)palladium II or palladium dichloride.
- the second additional sequence proceeds via an alkyne intermediate of the formula in which X, R, R1, and R3 are as above and R8 is hydrogen, C1-C7 alkyl, C1-C7 substituted alkyl, aryl, substituted aryl, aryl(C1-C3 alkyl), or substituted aryl (C1-C3 alkyl).
- R2 is C1-C8 alkyl, C1-C8 substituted alkyl, aryl-(C1-C4 alkyl), or substituted aryl(C1-C4 alkyl).
- the foregoing compounds of formula IV are prepared by reacting an iodo compound of the formula with a 1-alkyne in a suitable inert solvent and in the presence of a palladium catalyst such as tetrakis (triphenylphosphine)palladium or palladium dichloride.
- a palladium catalyst such as tetrakis (triphenylphosphine)palladium or palladium dichloride.
- Suitable catalysts are, for example, protic acids such as HCl, HBr and H2SO4 as well as mercury (II) salts.
- the compounds of this invention also include those in which the groups R and R3 taken together represent a -CH2CH2CH2- group. These compounds can be prepared from the corresponding bromo-substituted tetralones, chromanones, or thiochromanones.
- the foregoing bromo-substituted compound is reacted with pyrrolidine to form the corresponding 3-pyrrolidino-1,2-dihydronaphthalene, 3-pyrrolidinobenzpyran, or 3-pyrrolidinobenzthiopyran.
- the 3-pyrrolidino compound then is reacted with acrylamide to produce the corresponding cyclic amide bridging the 3,4-position and comprising the group -NH-CO-CH2-CH2-.
- the resulting product then is sequentially reduced, first using HSiEt3 and trifluoroacetic acid to reduce the 3,4 double bond and then using B2H6 or BH3 .
- SMe2 to reduce the cyclic amide carbonyl.
- the resulting product is a highly useful intermediate to the compounds of this invention.
- the intermediate is one in which X is -CH2-, -S-, or -O-, R1 is hydrogen, and R and R3 taken together represent a group of the formula -CH2CH2CH2-.
- the foregoing intermediates can be further modified by conversion of the group R1 from hydrogen to C1-C4 alkyl, allyl, cyclopropylmethyl, or aryl(C1-C4 alkyl) by reaction with the appropriate organic bromide or iodide.
- optically active isomers of the racemates of the invention are also considered part of this invention.
- Such optically active isomers may be prepared from their respective optically active precursors by the procedures described above, or by resolving the racemic mixtures. This resolution can be carried out in the presence of a resolving agent, by chromatography or by repeated crystallization.
- Particularly useful resolving agents are d- and l-tartaric acids, d- and l-ditoluoyltartaric acids, and the like.
- One particularly useful method for producing optically active isomers of the compounds of this invention is via an 8-substituted-2-tetralone, a 5-substituted-3-chromanone, or a 5-substituted-3-thiochromanone.
- Any of these intermediates may be reductively alkylated with an optically active ⁇ -phenethylamine after which the resulting mixture of diastereomers is separated by recognized methodology, such as chromatography. Cleavage of the ⁇ -phenethyl moiety produces a correspondingly substituted, optically active 2-amino-1,2,3,4-tetrahydronaphthalene, 3-aminochromane, or 3-aminothiochromane.
- Cleavage of the p -nitro- ⁇ -phenethyl moiety is achieved by reduction of the p-nitro group followed by acid-catalyzed solvolysis of the resulting p-amino- ⁇ -phenethyl moiety.
- Reduction of the nitro group can be accomplished by a wide range of reducing agents including, for example, titanium trichloride, lithium aluminum hydride, or zinc/acetic acid, or by catalytic hydrogenation.
- Solvolytic cleavage takes place when the monohydrochloride (or other monobasic salt) of the reduction product is treated with water or an alcohol at room temperature or, in some instances, at elevated temperatures.
- a particularly convenient condition for removing the p-nitro- ⁇ -phenethyl moiety is hydrogenation of the amine monohydrochloride in methanol over a platinum catalyst.
- the pharmaceutically acceptable acid addition salts of this invention are typically formed by reacting a 1,2,3,4-tetrahydronaphthalene, chromane, thiochromane sulfoxide, or thiochromane sulfone of this invention with an equimolar or excess amount of acid.
- the reactants are generally combined in a mutual solvent such as diethyl ether or benzene, and the salt normally precipitates out of solution within about one hour to 10 days, and can be isolated by filtration.
- n-Butyllithium (3.5 mmole, 3.0 ml, 1.2 M in hexane) was added to a solution of 8-bromo-2-di-n-propylamino-1,2,3,4-tetrahydronaphthalene (1.0 g, 3.2 mmol) in THF (10 ml) at -78°C.
- the reaction was stirred at -78°C for 45 min and then n-pentanal (0.41 ml, 3.9 mmole) was added. After stirring at -78°C for 5 min, the reaction was warmed to room temperature and poured into dilute HCl solution. The resulting solution was washed once with ether and the ether layer discarded.
- the aqueous layer was made basic with NH4OH solution and extracted with methylenechloride. The extract was dried (Na2SO4) and concentrated to give 0.95 g of the crude product.
- 2-Di-n-propylamino-8-bromo-1,2,3,4-tetrahydronaphthalene (5.0 g.; 16.1 mmole) was dissolved in 50 ml of THF, and the mixture was cooled to -78°C. after which 21.0 ml of n-butyllithium (0.92 M in hexane) were added. The mixture was stirred for 30 minutes, and 1.85 ml (21.0 mmole) of butyraldehyde were added. The mixture was allowed to warm to room temperature and was stirred overnight after which it was poured into water and extracted with methylene chloride. The extract was dried over sodium sulfate and evaporated to give 6.4 g of a residue.
- the oil was placed on a silica gel column and was eluted with a mixture of 3% methanol and methylene chloride containing a trace of ammonium hydroxide. The appropriate fractions were combined to obtain an oil which, when dissolved in ether, caused a brown precipitate to form. The precipitate was removed by filtration, and the filtrate was evaporated to give 3.0 g. of a light brown oil as the free base of the title compound.
- 2-Di-n-propylamino-8-bromo-1,2,3,4-tetrahydronaphthalene (1.0 g; 3.2 mmole) was dissolved in 10 ml of THF and cooled to -78°C after which 3.5 ml of n-butyllithium (1.0 M in hexane) were added. After 30 minutes, 0.53 ml (3.5 mmole) of ethyl isovalerate was added, and the mixture was warmed to -10°C and maintained for 30 minutes. The mixture then was poured into dilute acid, washed with ether, and the pH adjusted to 10. The mixture was extracted with methylene chloride, and the extract was dried over sodium sulfate and evaporated to give 0.83 g of a residue.
- 2-Di-n-propylamino-8-bromo-1,2,3,4-tetrahydronaphthalene (1.0 g; 3.2 mmole) was dissolved in 20 ml of THF and cooled to -78°C after which 4.7 ml of n-butyllithium (0.82 M in hexane) was added. The mixture was stirred for 30 minutes at -78°C after which 0.56 ml (4.2 mmole) of methyl trimethyl acetate was added. The mixture was allowed to warm to room temperature and then was poured into water and extracted with methylene chloride. The extract was dried over sodium sulfate and evaporated to give 1.6 g of a residue.
- 2-Di-n-propylamino-8-bromo-1,2,3,4-tetrahydronaphthalene (1.0 g; 3.2 mmole) was dissolved in 10 ml of THF and cooled to -78°C after which 2.8 ml of n-butyllithium (1.27 M in hexane) were added. The mixture was stirred at -78°C for 45 minutes after which 0.59 ml (3.5 mmole) of ethyl cyclohexanecarboxylate was added.
- the mixture was warmed to room temperature and then was poured into a 10% hydrochloric acid solution, washed with ether, the pH adjusted to 10 with ammonium hydroxide, and extracted with methylene chloride. The extract was dried over sodium sulfate and evaporated to give 0.8 g of a residue.
- Butyllithium (1.2 M in hexane, 3.0 ml, 3.5 mmole) was added to a solution of 8-bromo-2-di-n-propylamino-1,2,3,4-tetrahydronaphthylene (1.0 g, 3.2 mmole) in THF (10 ml) at -78° and stirred for 45 minutes. Cyclohexanecarboxaldehyde (0.47 ml, 3.9 mmole) was added. The reaction was stirred at -78° for five minutes, warmed to room temperature, poured into dilute HCl solution and washed with ether. The aqueous layer was made basic with NH4OH and extracted with methylene chloride.
- the extract was dried (Na2SO4) and concentrated to give 1.1 g of the crude product.
- the crude product was dissolved in methylene chloride (50 ml) and molecular sieves and pyridinium chlorochromate (1.4 g, 6.4 mmole) added. The reaction was stirred at room temperature for two hours. Methanol (50 ml) was added and the reaction concentrated to provide a slurry. The slurry was dissolved in methylene chloride (50 ml) and enough ether was added to give a cloudy solution. This material was added to a pad of silica gel and eluted with ether.
- the silica gel pad was eluted with 10% methanol in methylene chloride and the eluent concentrated to give an oily residue. This material was triturated with methanol and filtered through Celite. This filtrate was combined with the ether solution from above and concentrated. This material was dissolved in methylene chloride. Ether was added until the solution became cloudy and then filtered through florisil. The filtrate was concentrated to give 560 mg of an oil which was purified by silica gel flash chromatography using 3:1 hexane:ether containing a trace of NH4OH as solvent. Appropriate fractions were combined and concentrated to give 350 mg of the desired compound. The oxalate salt was formed and crystallized from ethyl acetate/hexane to give 370 mg of a white solid. m.p. 98.5-100°. Elemental Analysis:
- 2-Di-n-propylamino-8-bromo-1,2,3,4-tetrahydronaphthalene (1.0 g; 3.2 mmole) was dissolved in 10 ml of THF and cooled to -78°C after which 3.5 ml of n-butyllithium (1.0 M in hexane) were added. The mixture was stirred for one hour at -78°C after which 680 mg (1.5 equivalents) of 4-chlorobenzaldehyde in THF were added. The mixture was stirred for 15 minutes at -78°C and then was allowed to warm to room temperature.
- the mixture was poured into a 10% aqueous hydrochloric acid solution, washed with ether, the pH adjusted to 10 with ammonium hydroxide, and extracted with methylene chloride. The extract was dried over sodium sulfate and evaporated to give 1.5 g of a residue.
- the aqueous layer was made basic with NaOH and extracted with methylene chloride.
- the basic extract was dried (Na2SO4) and concentrated to give 200 mg of residue which by nmr did not contain product.
- the extract from the acidic material was dried (Na2SO4) and concentrated to give 2.0 g of a residue.
- Purification of this material by flash silica gel chromatography using 1:1 ether:hexane containing a trace of ammonium hydroxide as solvent provided the free base of the title compound (340 mg).
- the salt of 130 mg of this material with p-toluene sulfonic acid was prepared and crystallized from ethyl acetate/ether to provide 118 mg of the title compound. m.p. 107-109°C. Elemental Analysis:
- the oxalic acid salt was formed and three times recrystallized from ethyl acetate to give the salt as a white powder, m.p. 118°C.
- Butyllithium (1.2M in hexane; 2.8 ml; 3.4 mmol) was added to a solution of 8-bromo-2-di-n-propylamino-1,2,3,4-tetrahydronaphthalene (1 g; 3.22 mmol) in THF (50 ml) at -78°C. After 1.5 hr., a solution of trimethyltin chloride (1.3 g, 2.0 mmol) in THF (20 ml) was added. The reaction mixture was allowed to warm to room temperature, stirred overnight at room temperature, poured into water, and extracted with methylene chloride. The extract was dried (Na2SO4) and concentrated to give the crude product. Purification by chromatography using 1:10 methanol:methylene chloride gave 1.2 g of the desired product which was used directly in the next step.
- Bis-triphenylphosphine palladium dichloride 120 mg was added to a solution of 2-dipropylamino-8-trimethylstannyl-1,2,3,4-tetrahydronaphthalene (500 mg, 1.27 mmol) in benzene (20 ml). Methoxyacetyl chloride (1.5 ml; 1.77 g; 16.5 mmol) was added. The reaction mixture was stirred at room temperature overnight and then heated to reflux for 5 hr. The reaction mixture was poured into water and extracted with methylene chloride. The extract was dried (MgSO4) and concentrated to give 800 mg of crude product. Purification by chromatography using 1:10 methanol: methylene chloride as solvent gave 380 mg of 2-di-n-propylamino-8-methoxyacetyl-1,2,3,4-tetrahydronaphthalene.
- n-butyllithium (1.6 M in hexane, 15.1 ml, 24.2 mmole) was added to a solution of 8-bromo-2-di-n-propylamino-1,2,3,4-tetrahydronaphthalene (5.0 g, 16.1 mmole) in THF (50 ml) at -78° and the reaction stirred at -78° for one hour. Gaseous carbon dioxide was bubbled through the reaction at -78° until the deep violet color which forms dissipates. Methyllithium (1.4 M in ether, 23 ml) was added. The reaction was stirred at -78° for 30 minutes and warmed to room temperature.
- the reaction was stirred for an additional ten minutes at room temperature at which time the pink color had been lost. An additional 10 ml of the methyllithium solution was added and the reaction became pink once again. After 15 minutes, the pink color was lost and an additional 10 ml of the methyllithium solution added.
- the reaction was poured onto ice, made acidic with hydrochloric acid and extracted with ether. The aqueous layer was made basic and extracted with methylenechloride. The basic extracts were dried (Na2SO4) and concentrated to give 3.8 g of crude product. Purification by flash silica gel chromatography using 2:1 hexane:ether containing trace ammonium hydroxide provided the free base of the title compound as a yellow oil (2.7 g, 61%).
- the maleate salt was prepared and crystallized from methanol/ethyl acetate/hexane to give the maleate salt. m.p. 115-116°. Elemental Analysis:
- the hydrochloride salt can be prepared. Crystallization from ethanol/ether provided the hydrochloride salt as colorless crystals. m.p. 124-125°C. Elemental Analysis:
- n-Butyllithium (1.6 M in hexane, 60.5 ml, 96.8 mmole) was added to a solution of 8-bromo-2-di-n-propylamino-1,2,3,4-tetrahydronaphthalene (20.0 g, 64.5 mmole) in THF (200 ml) at -78° and the reaction stirred at -78° for one hour.
- Acetaldehyde (4.3 ml, 77.4 mmole) was added and the reaction allowed to warm to room temperature.
- the reaction was poured into water, made basic with ammonium hydroxide and extracted with methylene chloride. The extract was dried (Na2SO4) and concentrated to give 21.4 g of a yellow oil.
- another embodiment of the present invention is a method of effecting agonist action at the 5-HT 1A receptors which comprises administering to a mammal in need thereof a pharmaceutically effective amount of a compound of the invention.
- pharmaceutically effective amount represents an amount of a compound of the invention which is capable of binding to serotonin 1A receptors.
- the specific dose of compound administered according to this invention will, of course, be determined by the particular circumstances surrounding the case, including, for example, the compound administered, the route of administration, and the condition being treated.
- a typical daily dose generally will contain from about 0.01 mg/kg to about 20 mg/kg of the active compound of this invention.
- Preferred daily doses generally will be from about 0.05 to about 10 mg/kg, and ideally from about 0.1 to about 5 mg/kg.
- the compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal.
- routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal.
- a special feature of the compounds of this invention is that they are extremely selective in effecting agonist action at serotonin 1A receptors relative to other serotonin receptors.
- the compounds of this invention are believed to have the ability to treat in mammals a variety of 5-HT mediated states and disorders such as sexual disorders, eating disorders, depression, alcoholism, pain, senile dementia, anxiety, and smoking. Therefore, the present invention also provides methods of treating the above disorders at rates set forth above for agonist action in mammals at 5-HT receptors.
- mice Male Sprague-Dawley rats (110-150 g) from Harlan Industries (Cumberland, IN) were fed a Purina Chow ad libitum for at least 3 days before being used in the studies. Rats were killed by decapitation. The brains were rapidly removed, and the cerebral cortices were dissected out at 4°C.
- Binding of (3H-8-OH-DPAT) was performed according to the previously described method [Wong et al ., J. Neural Transm . 64 :251-269 (1985)]. Briefly, synaptosomal membranes isolated from cerebral cortex were incubated at 37°C for 10 min. in 2 ml of 50 mM Tris-HCl, pH 7.4; 10 ⁇ M pargyline; 0.6 mM ascorbic acid; 0.4 nM 3H-8-OH-DPAT; and from 1 to 1000 nM of test compound. Binding was terminated by filtering samples under reduced pressure through glass fiber (GFB) filters.
- GFB glass fiber
- the filters were washed twice with 5 ml of ice cold buffer and placed in scintillation vials with 10 ml of PCS (Amersham/Searle) scintillation fluid. Radioactivity was measured with a liquid scintillation spectrometer. Unlabeled 8-OH-DPAT at 10 ⁇ M was also included in separate samples to establish non-specific binding. Specific binding of 3H-8-OH-DPAT is defined as the difference of radioactivity bound in the absence and in the presence of 10 ⁇ M unlabeled 8-OH-DPAT.
- Table I The results of the evaluation of various compounds of the present invention are set forth below in Table I.
- the first column provides the Example Number of the compound evaluated; the next 7 columns identify the structure of the compound evaluated when taken with the formula set forth in the heading; the next-succeeding column identifies the salt form of the compound evaluated; and the final column provides the amount of the test compound expressed in nanomolar concentration required to inhibit the binding of 3H-8-OH-DPAT) by 50%, and is indicated in Table I as IC50.
- Another embodiment of the present invention is a pharmaceutical formulation comprising a compound of the invention and a pharmaceutically acceptable carrier, diluent or excipient therefor.
- the active ingredient will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, paper or other container.
- a carrier which may be in the form of a capsule, sachet, paper or other container.
- the carrier serves as a diluent, it may be a solid, semisolid or liquid material which acts as a vehicle, excipient or medium for the active ingredient.
- compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, sterile packaged powders, and the like.
- Suitable carriers, excipients, and diluents are lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water syrup, methyl cellulose, methyl-hydroxybenzoates, propyl hydroxybenzoates, talc, magnesium stearate, and mineral oil.
- the formulations may additionally include lubricating agents, wetting agents, emulsifying agents, suspending agents, preserving agents, sweetening agents, flavoring agents, and the like.
- the compositions of the invention may be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.
- compositions are preferably formulated in a unit dosage form, each dosage generally containing from about 0.1 to about 500 mg, and preferably from about 1 to about 250 mg, of the active ingredient.
- unit dosage form refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier.
- Hard gelatin capsules are prepared using the following ingredients:
- the above ingredients are mixed and filled into hard gelatin capsules in 460 mg quantities.
- a tablet is prepared using the ingredients below: The components are blended and compressed to form tablets each weighing 665 mg.
- An aerosol solution is prepared containing the following components:
- the active compound is mixed with ethanol and the mixture added to a portion of the propellant 22, cooled to -30°C. and transferred to a filling device. The required amount is then fed to a stainless steel container and diluted with the remainder of the propellant. The valve units are then fitted to the container.
- Tablets each containing 60 mg of active ingredient, are made as follows:
- the active ingredient, starch and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly.
- the aqueous solution containing polyvinylpyrrolidone is mixed with the resultant powder, and the mixture then is passed through a No. 14 mesh U.S. sieve.
- the granules so produced are dried at 50°C and passed through a No. 18 mesh U.S. sieve.
- the sodium carboxymethyl starch, magnesium stearate and talc, previously passed through a No. 60 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg.
- Capsules each containing 80 mg of active ingredient, are made as follows:
- the active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No. 45 mesh U.S. sieve, and filled into hard gelatin capsules in 200 mg quantities.
- Suppositories each containing 225 mg of active ingredient, are made as follows:
- the active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2 g capacity and allowed to cool.
- Suspensions each containing 50 mg of active ingredient per 5 ml dose, are made as follows:
- the active ingredient is passed through a No. 45 mesh U.S. sieve and mixed with the sodium carboxymethyl cellulose and syrup to form a smooth paste.
- the benzoic acid solution, flavor and color are diluted with a portion of the water and added, with stirring. Sufficient water is then added to produce the required volume.
- An intravenous formulation may be prepared as follows:
- the solution of the above ingredients generally is administered intravenously at a rate of 1 ml per minute to a subject suffering from depression.
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Abstract
in which R is C₁-C₄ alkyl, C₃-C₄ alkenyl, or cyclopropylmethyl;
R₃ is hydrogen; or
R and R₃ taken together are a divalent group of the formula -CH₂CH₂CH₂-;
R₁ is hydrogen, C₁-C₄ alkyl, C₃-C₄ alkenyl, cyclopropylmethyl, aryl(C₁-C₄-alkyl), -COR₄, -(CH₂)nS(C₁-C₄ alkyl) or -(CH₂)nCONR₅R₆;
n is an integer from 1 to 4;
R₄ is hydrogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, or phenyl;
R₅ and R₆ are independently hydrogen, C₁-C₄ alkyl, or C₃-C₇ cycloalkyl with the proviso that when one of R₅ or R₆ is cycloalkyl the other is hydrogen;
X is -CH₂-, -O-, -S-,
A is
R₂ is C₁-C₈ alkyl, substituted C₁-C₈ alkyl, C₂-C₄ alkenyl, aryl, substituted aryl, aryl(C₁-C₄-alkyl), substituted aryl(C₁-C₄ alkyl), C₃-C₇ cycloalkyl-substituted methyl, or C₃-C₇ cycloalkyl;
and pharmaceutically acceptable acid addition salts thereof.
Description
- Over the last several years it has become apparent that the neurotransmitter serotonin (5-hydroxy-tryptamine -- 5-HT) is associated directly or indirectly with a number of physiological phenomena, including appetite, memory, thermoregulation, sleep, sexual behavior, anxiety, depression, and hallucogenic behavior [Glennon, R. A., J. Med. Chem. 30, 1 (1987)].
- It has been recognized that there are multiple types of 5-HT receptors. These receptors have been classified as 5-HT₁, 5-HT₂, and 5-HT₃ receptors, with the former being further divided into the sub-classes 5-HT1A, 5-HT1B, 5-HT1C, and 5-HT1D.
- Selected 2-amino-1,2,3,4-tetrahydronaphthalenes (2-aminotetralins) and 3-aminochromanes have been shown to exhibit binding affinity at the 5-HT1A receptor.
- Co-pending application Serial No. 315,750 filed February 27, 1989, describes certain 2-aminotetralins substituted in the 8-position by formyl, cyano, halo, hydroxymethyl, carboxamido, carboxyl, or alkoxycarbonyl. The compounds are described as exhibiting high binding affinity at the 5-HT1A receptor. 2-aminotetralins in which the 8-position is substituted by, among others, formyl, are also described in EPO Patent Application No. 272,534. In addition, co-pending application Serial No. 315,752 filed February 27, 1989, describes other 2-aminotetralins substituted in the 8-position and 3-aminochromanes substituted in the 5-position by sulfides, sulfoxides, and sulfones. These compounds, as well, are described as having binding affinity at the 5-HT1A receptor.
- Another class of 2-aminotetralins are described in European Patent Application No. 343,830, published November 29, 1989. These compounds have a piperazinyl or homopiperazinyl moiety in the 2-position and, distinct from the foregoing tetralins, do not exhibit affinity for serotonin receptors but rather inhibit the re-uptake of serotonin. We have now discovered a further class of compounds which, by reason of their 5-HT1A agonist activity, are useful in the treatment, for example, of sexual dysfunction, anxiety, depression, obsessive-compulsive behavior, cognition disorders, emesis, drug abuse, hypertension, excess acid secretion, and eating disorders, such as anorexia.
- The present invention provides novel ring-substituted 2-amino-1,2,3,4-tetrahydronaphthalenes and 3-aminochromanes which are selective agonists at the 5-HT1A receptor.
- More specifically, this invention is directed to a compound of the formula
in which R is C₁-C₄ alkyl, C₃-C₄ alkenyl, or cyclopropylmethyl;
R₃ is hydrogen; or
R and R₃ taken together are a divalent group of the formula -CH₂CH₂CH₂-;
R₁ is hydrogen, C₁-C₄ alkyl, C₃-C₄ alkenyl, cyclopropylmethyl, aryl(C₁-C₄-alkyl), -COR₄, -(CH₂)nS(C₁-C₄ alkyl) or -(CH₂)nCONR₅R₆;
n is an integer from 1 to 4;
R₄ is hydrogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, or phenyl;
R₅ and R₆ are independently hydrogen, a C₁-C₄ alkyl, or C₃-C₇ cycloalkyl with the proviso that when one of R₅ or R₆ is cycloalkyl the other is hydrogen;
X is -CH₂-, -O-, -S-,
A is
R₂ is C₁-C₈ alkyl, substituted C₁-C₈ alkyl, C₂-C₄ alkenyl, aryl, substituted aryl, aryl(C₁-C₄-alkyl), substituted aryl(C₁-C₄ alkyl), C₃-C₇ cycloalkyl-substituted methyl, or C₃-C₇ cycloalkyl;
and pharmaceutically acceptable acid addition salts thereof. - This invention also provides a pharmaceutical formulation which comprises, in association with a pharmaceutically acceptable carrier, diluent, or excipient, a compound of the formula
in which R is C₁-C₄ alkyl, C₃-C₄ alkenyl or cyclopropylmethyl;
R₃ is hydrogen; or
R and R₃ taken together are a divalent group of the formula -CH₂CH₂CH₂-;
R₁ is hydrogen, C₁-C₄ alkyl, C₃-C₄ alkenyl, cyclopropylmethyl, aryl(C₁-C₄-alkyl), -COR₄, -(CH₂)nS(C₁-C₄ alkyl) or -(CH₂)nCONR₅R₆;
n is an integer from 1 to 4;
R₄ is hydrogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, or phenyl;
R₅ and R₆ are independently hydrogen, C₁-C₄ alkyl, or C₃-C₇ cycloalkyl with the proviso that when one of R₅ or R₆ is cycloalkyl the other is hydrogen;
X is -CH₂-, -O-, -S-,
R₂ is C₁-C₈ alkyl, substituted C₁-C₈ alkyl, C₂-C₄ alkenyl, aryl, substituted aryl, aryl(C₁-C₄-alkyl), substituted aryl(C₁-C₄ alkyl), C₃-C₇ cycloalkyl-substituted methyl, or C₃-C₇ cycloalkyl;
and pharmaceutically acceptable acid addition salts thereof. - A further embodiment of the invention is a method for effecting a biological response at the 5-HT1A receptor. More particularly, further embodiments are methods for treating a variety of disorders in mammals which may be treated by stimulating 5-HT1A receptors. Included among these disorders are anxiety, depression, sexual dysfunction, obsessive-compulsive behavior, hypertension, excess acid secretion, and eating disorders. Any of these methods employ a compound of the formula
in which R is C₁-C₄ alkyl, C₃-C₄ alkenyl or cyclopropylmethyl;
R₃ is hydrogen; or
R and R₃ taken together are a divalent group of the formula -CH₂CH₂CH₂-;
R₁ is hydrogen, C₁-C₄ alkyl, C₃-C₄ alkenyl, cyclopropylmethyl, aryl(C₁-C₄-alkyl), -COR₄, -(CH₂)nS(C₁-C₄ alkyl) or -(CH₂)nCONR₅R₆;
n is an integer from 1 to 4;
R₄ is hydrogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, or phenyl;
R₅ and R₆ are independently hydrogen, C₁-C₄ alkyl, or C₃-C₇ cycloalkyl with the proviso that when one of R₅ or R₆ is cycloalkyl the other is hydrogen;
X is -CH₂-, -O-, -S-,
R₂ is C₁-C₈ alkyl, substituted C₁-C₈ alkyl, C₂-C₄ alkenyl, aryl, substituted aryl, aryl(C₁-C₄-alkyl), substituted aryl(C₁-C₄ alkyl), C₃-C₇ cycloalkyl-substituted methyl, or C₃-C₇ cycloalkyl;
and pharmaceutically acceptable acid addition salts thereof. - In the above formulas, the term "C₁-C₄ alkyl" means a straight or branched alkyl chain having from one to four carbon atoms. Such C₁-C₄ alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl.
- The term "C₁-C₈ alkyl" means a straight or branched alkyl chain having from one to eight carbon atoms. Groups which are included in such term are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 4-methylpentyl, n-heptyl, 3-ethylpentyl, 2-methylhexyl, 2,3-dimethylpentyl, n-octyl, 3-propylpentyl, 6-methylheptyl, and the like.
- The term "C₁-C₄ alkoxy" means any of methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, and sec-butoxy.
- The term "aryl" means an aromatic carbocyclic structure. Examples of such ring structures are phenyl, naphthyl, and the like.
- The term "C₃-C₇ cycloalkyl" means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
- The term "aryl (C₁-C₄ alkyl)" means an aromatic carbocyclic structure joined to a C₁-C₄ alkyl group. Examples of such groups are benzyl, phenylethyl, α-methylbenzyl, 3-phenylpropyl, α-naphthylmethyl, β-naphthylmethyl, 4-phenylbutyl, and the like.
- The term "C₂-C₄ alkenyl" means a straight or branched hydrocarbon chain having from two to four carbon atoms and containing one double bond. Groups which are included in such terms are vinyl, 1-methylvinyl, 2-methylvinyl, allyl, 2-butenyl, 3-butenyl, 1-butenyl, 1-methylallyl, 2-methylallyl, and the like.
- For purposes herein, the term "C₃-C₄ alkenyl" is specifically defined to mean any of allyl, 2-butenyl, 3-butenyl, and 2-methylallyl.
- In addition, the C₁-C₈ alkyl, the aryl, and the aryl (C₁-C₄ alkyl) groups may be substituted by one or two moieties. Typical aryl and/or alkyl substituents are C₁-C₃ alkoxy, halo, hydroxy, C₁-C₃ thioalkyl, and the like. Moreover, the aryl and aryl (C₁-C₄ alkyl) groups may also be substituted by a C₁-C₃ alkyl or a trifluoromethyl group.
- In the foregoing, the term "C₁-C₃ alkyl" means any of methyl, ethyl, n-propyl, and isopropyl; the term "C₁-C₃ alkoxy" means any of methoxy, ethoxy, n-propoxy, and isopropoxy; the term "halo" means any of fluoro, chloro, bromo, and iodo; and the term "C₁-C₃ thioalkyl" means any of methylthio, ethylthio, n-propylthio, and isopropylthio.
- Examples of substituted C₁-C₈ alkyl are methoxymethyl, trifluoromethyl, 6-chlorohexyl, 2-bromopropyl, 2-ethoxy-4-iodobutyl, 3-hydroxypentyl, methylthiomethyl, and the like.
- Examples of substituted aryl are p-bromophenyl, m-iodophenyl, p-tolyl, o-hydroxyphenyl, β-(4-hydroxy)naphthyl, p-(methylthio)phenyl, m-trifluoromethylphenyl, 2-chloro-4-methoxyphenyl, α-(5-chloro)naphthyl, and the like.
- Examples of substituted aryl (C₁-C₄ alkyl) are p-chlorobenzyl, o-methoxybenzyl, m-(methylthio)-α-methylbenzyl, 3-(4′-trifluoromethylphenyl)-propyl, o-iodobenzyl, p-methylbenzyl, and the like.
- While all of the compounds of the present invention are useful for treating a variety of disorders by virtue of their ability to activate the 5-HT1A receptor in mammals, certain of the compounds are preferred.
-
- Moreover, R and R₁ preferably are both C₁-C₄ alkyl, and, more preferably, both are n-propyl.
- X preferably is -CH₂-.
- R₂ preferably is C₁-C₈ alkyl, and, more preferably, C₁-C₅ alkyl. Most preferably, R₂ is t-butyl.
- The compounds of the present invention possess an asymmetric carbon represented by the carbon atom labeled with an asterisk in the following formula:
As such, each of the compounds exists as its individual d- and l-stereoisomers and also as the racemic mixture of such isomers. Accordingly, the compounds of the present invention include not only the dl-racemates but also their respective optically active d- and l-isomers. -
- Since the compounds of this invention are amines, they are basic in nature and accordingly react with any of a number of inorganic and organic acids to form pharmaceutically acceptable acid addition salts. Since the free amines of the compounds of this invention are typically oils at room temperature, it is preferable to convert the free amines to their corresponding pharmaceutically acceptable acid addition salts for ease of handling and administration, since the latter are routinely solid at room temperature. Acids commonly employed to form such salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as maleic, fumaric, p-toluenesulfonic, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like. Examples of such pharmaceutically acceptable salts thus are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, γ-hydroxybutyrate, glycollate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, and the like. Preferred pharmaceutically acceptable acid addition salts are those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid.
- In addition, some of these salts may form solvates with water or organic solvents such as ethanol. Such solvates also are included as compounds of this invention.
- The following compounds further illustrate compounds contemplated within the scope of this invention:
2-(Di-n-propylamino)-8-acetyl-1,2,3,4-tetrahydronaphthalene;
2-Ethylamino-8-benzoyl-1,2,3,4-tetrahydronaphthalene;
2-(N-Methyl-N-benzylamino)-8-isobutyryl-1,2,3,4-tetrahydronaphthalene;
2-Diallylamino-8-phenylacetyl-1,2,3,4-tetrahydronaphthalene;
2-Diethylamino-8-(p-methoxybenzoyl)-1,2,3,4-tetrahydronaphthalene;
2-(Di-n-propylamino)-8-trifluoroacetyl-1,2,3,4-tetrahydronaphthalene;
2-Benzylmethylamino-8-heptanoyl-1,2,3,4-tetrahydronaphthalene;
2-(Di-n-propylamino)-8-(α-methylpropionyl)-1,2,3,4-tetrahydronaphthalene;
2-Dimethylamino-8-cyclohexylcarbonyl-1,2,3,4-tetrahydronaphthalene;
2-(Di-cyclopropylmethylamino)-8-(β-chloropentanoyl)-1,2,3,4-tetrahydronaphthalene;
2-(Di-n-propylamino)-8-(p-chlorophenylacetyl)-thio-1,2,3,4-tetrahydronaphthalene;
2-Ethylamino-8-propionyl-1,2,3,4-tetrahydronaphthalene;
2-n-Butylamino-8-(α,α-dimethylpropionyl)-1,2,3,4-tetrahydronaphthalene;
2-(Di-n-propylamino)-8-[β-(4′-methoxyphenyl)-propionyl]-1,2,3,4-tetrahydronaphthalene;
2-(Di-n-propylamino)-8-(α,α-dimethylbutyryl)-1,2,3,4-tetrahydronaphthalene;
3-(Di-n-propylamino)-5-acetyl-chromane; and the like. - The compounds of the present invention may be prepared by procedures well known to those of ordinary skill in the art. The compounds in which X is -CH₂- and R₃ is hydrogen preferably are synthesized by preparation of an 8-bromo-2-tetralone. The 8-bromo-2-tetralone then is reductively aminated with the desired amine to produce the desired 2-amino-8-bromotetralin intermediate. The 8-bromo intermediate then is treated to produce the desired product directly or via the corresponding compound in which the group in the 8-position is R₂CH(OH)-.
- Schemes for these reactions are as follows:
- A. Synthesis of 8-Bromo-2-tetralone
- B. Reductive Amination
- C. Replacement of Bromo Ring Substituent Via Lithiation
- D. Transformation of a Carbonyl Derivative to a Compound of this Invention.
- As depicted above, the 8-bromo-2-tetralones represent intermediates which, when reductively aminated and treated, via lithiation, with the appropriate reagent, result in compounds of this invention. When, for example, the reaction involves the use of an aldehyde, the product which results, although having activity in its own right, is, in general, an intermediate of formula I (A is =CHOH) to the preparation of the final product. When the reaction involves the use of an ester, the product is the final product itself (A is =C=O).
- The tetralones are available by any of a wide range of recognized methods. For example, they can be produced by a Friedel-Crafts reaction of an appropriately ring-substituted phenylacetyl chloride with ethylene in the presence of aluminum chloride.
- The tetralone, once formed, can, by simple reductive amination using the selected amine, be converted to a 2-amino-8-bromo-1,2,3,4-tetrahydronaphthalene useful as an intermediate to a compound of this invention. The tetralone is first reacted with the amine to form the corresponding enamine after which the enamine is reduced with sodium borohydride to the tetrahydronaphthalene.
- The 2-amino-8-bromo-1,2,3,4-tetrahydronaphthalene can be used to produce compounds of this invention by formation of a lithium intermediate via a lithiation reaction using an alkyllithium, preferably n-butyllithium. The reactive lithium intermediate then is treated with an appropriate carbonyl compound to produce either the ketone directly or a precursor of the ketone. Hence, treatment of the 8-lithio tetralin with a compound R₂COZ, where Z is halo, alkoxy, hydroxy, aryloxy, -S-(C₁-C₃ alkyl),-OCO₂R′,
and the like, will, upon workup, yield the desired ketone. - Alternatively, treatment of the 8-lithiotetralin with carbon dioxide and then treatment of the resulting carboxylate with an organolithium reagent, e.g., methyllithium, provides the corresponding ketone. A further alternative synthesis entails reacting the 8-lithiotetralin with an appropriate aldehyde to yield an alcohol of formula I (A=CHOH) which is subsequently oxidized to the ketone. The aforementioned alcohol can also be prepared by addition of a suitable organo-metallic reagent (R₂M in which M is Li, MgW, ZnW, and the like, W being an appropriate halide) to an 8-formyl-2-aminotetralin. The 8-formyl-2-aminotetralin is prepared by addition of the 8-lithio-2-aminotetralin to dimethylformamide with aqueous workup of the resulting product.
- In another approach, the 8-bromo-2-tetralone can first be protected and the bromo substituent converted to the appropriate ketone as described above. The resulting 8-acyl-2-tetralone, after deprotection, can then be reductively aminated to a compound of this invention.
- In the foregoing reactions, the 8-lithio tetralin may be replaced by the corresponding Grignard reagent to yield the desired product.
- The compounds of this invention in which X is oxygen are available by reductive amination and bromo replacement as in the foregoing, but using 5-bromo-3-chromanone. The latter can be produced by a sequence of reactions beginning with m-bromophenol. Briefly, m-bromophenol is treated with allyl bromide in the presence of potassium carbonate to produce allyl 3-bromophenyl ether. The ether is converted to 2-allyl-3-bromophenol upon heating it in the presence of N,N-dimethylaniline. The phenol, upon reaction with ethyl chloroacetate, is converted to the ethyl ester of 2-allyl-3-(carboxymethoxy)bromobenzene. Upon oxidation using ozone followed by reductive work up, the allyl group is converted to a formylmethyl substituent which is then further oxidized using Jones' Reagent to the carboxymethyl substituent, the resulting product being the ethyl ester of (2-carboxymethyl-3-bromo)phenoxyacetic acid. The partial ester is converted to the diethyl ester using ethanol and gaseous hydrogen chloride. In the presence of potassium t-butoxide, the diester is cyclized to a mixture of 4-ethoxycarbonyl-5-bromo-3-chromanone and 2-ethoxycarbonyl-5-bromo-3-chromanone. Upon heating in the presence of acid, the latter is converted to 5-bromo-3-chromanone.
- An alternate and improved synthesis of the 5-bromo-3-chromanone involves a sequence of reactions beginning with the ethyl ester of (2-allyl-3-carboxymethoxy)bromobenzene. The bromobenzene is oxidized using ozone to form, upon work-up with dimethyl thioether, the ethyl ester of (2-formylmethyl-3-carboxymethoxy)bromobenzene. The formylmethyl substituent is further oxidized to carboxymethyl using Jones' Reagent, the resulting product being (2-bromo-6-ethoxycarbonylmethoxy)phenylacetic acid. The acid is esterified to the t-butyl ester using t-butyl acetate and sulfuric acid, after which the resulting diester is cyclized in the presence of potassium t-butoxide to 4-t-butoxycarbonyl-5-bromo-3-chromanone. The t-butoxycarbonyl group then is cleaved using trifluoroacetic acid with formation of the desired 5-bromo-3-chromanone.
- The compounds of this invention in which X is sulfur are available by bromo replacement of the corresponding 2-amino-5-bromothiochromanes. The latter are available by a sequence of reactions beginning with m-bromothiophenol. The thiophenol is treated in base with β-chloropropionic acid to produce m-bromophenylthiopropionic acid. The acid then is cyclized with polyphosphoric acid or with thionyl chloride or phosgene and a Lewis acid to produce a mixture of 5-bromo-4-thiochromanone and 7-bromo-4-thiochromanone. The thiochromanone mixture is reduced using, for example, sodium borohydride, to produce 4-bromo-1,2-benzothiapyran which is then oxidized with an organic peroxide to the corresponding sulfoxide having an epoxy group in the 3,4 position. Upon treatment with a Lewis acid, 5-bromo-3-thiochromanone sulfoxide is formed which can be reduced to the corresponding thiochromanone using dimethyl sulfide in the presence of trifluroacetic anhydride, oxalyl chloride, thionyl chloride, and the like, or reductively aminated to the 3-amino-5-bromothiochromane sulfoxide by treatment with the appropriate amine and sodium borohydride. The latter is reduced to the desired 3-amino-5-bromothiochromane using trifluoroacetic anhydride.
- Two additional alternative syntheses of the compounds of this invention are via each of two novel intermediates, both of which are part of this invention. The starting material in both sequences is the previously-described bromo compound in which X, R, R₁, and R₃ are as herein defined.
-
- The foregoing compounds of formula III are prepared by reacting the corresponding bromo compound with n-butyllithium and treating the resulting lithio derivative with chlorotri(C₁-C₄ alkyl)stannane.
- The stannyl intermediate then is reacted with an acyl chloride in the presence of a suitable catalyst such as dichlorobis(triphenylphosphine)palladium II or palladium dichloride. This reaction is described in Yamamoto and Yanagi, Chem. Pharm. Bull. 30(6), 2003 (1982), Milstein and Stille, J. Am. Chem. Soc. 100, 3636 (1978) and J. Org. Chem. 44, 1613 (1979).
- The second additional sequence proceeds via an alkyne intermediate of the formula
in which X, R, R₁, and R₃ are as above and R₈ is hydrogen, C₁-C₇ alkyl, C₁-C₇ substituted alkyl, aryl, substituted aryl, aryl(C₁-C₃ alkyl), or substituted aryl (C₁-C₃ alkyl). The sequence is useful in preparing compounds of this invention in which R₂ is C₁-C₈ alkyl, C₁-C₈ substituted alkyl, aryl-(C₁-C₄ alkyl), or substituted aryl(C₁-C₄ alkyl). -
- The resulting alkyne is converted to a compound of this invention by hydration in the presence of a suitable catalyst. Suitable catalysts are, for example, protic acids such as HCl, HBr and H₂SO₄ as well as mercury (II) salts.
- The compounds of this invention also include those in which the groups R and R₃ taken together represent a -CH₂CH₂CH₂- group. These compounds can be prepared from the corresponding bromo-substituted tetralones, chromanones, or thiochromanones.
- The foregoing bromo-substituted compound is reacted with pyrrolidine to form the corresponding 3-pyrrolidino-1,2-dihydronaphthalene, 3-pyrrolidinobenzpyran, or 3-pyrrolidinobenzthiopyran. The 3-pyrrolidino compound then is reacted with acrylamide to produce the corresponding cyclic amide bridging the 3,4-position and comprising the group -NH-CO-CH₂-CH₂-. The resulting product then is sequentially reduced, first using HSiEt₃ and trifluoroacetic acid to reduce the 3,4 double bond and then using B₂H₆ or BH₃.SMe₂ to reduce the cyclic amide carbonyl. The resulting product is a highly useful intermediate to the compounds of this invention. The intermediate is one in which X is -CH₂-, -S-, or -O-, R₁ is hydrogen, and R and R₃ taken together represent a group of the formula -CH₂CH₂CH₂-. Moreover, the intermediate contains a bromo substituent at the 8-position of the tetralin (X = -CH₂-) or the 5-position of the chromane (X = O) or thiochromane (X = S).
- The foregoing intermediates can be further modified by conversion of the group R₁ from hydrogen to C₁-C₄ alkyl, allyl, cyclopropylmethyl, or aryl(C₁-C₄ alkyl) by reaction with the appropriate organic bromide or iodide.
-
- The optically active isomers of the racemates of the invention are also considered part of this invention. Such optically active isomers may be prepared from their respective optically active precursors by the procedures described above, or by resolving the racemic mixtures. This resolution can be carried out in the presence of a resolving agent, by chromatography or by repeated crystallization. Particularly useful resolving agents are d- and l-tartaric acids, d- and l-ditoluoyltartaric acids, and the like.
- One particularly useful method for producing optically active isomers of the compounds of this invention is via an 8-substituted-2-tetralone, a 5-substituted-3-chromanone, or a 5-substituted-3-thiochromanone. Any of these intermediates may be reductively alkylated with an optically active α-phenethylamine after which the resulting mixture of diastereomers is separated by recognized methodology, such as chromatography. Cleavage of the α-phenethyl moiety produces a correspondingly substituted, optically active 2-amino-1,2,3,4-tetrahydronaphthalene, 3-aminochromane, or 3-aminothiochromane.
- The conditions necessary for removing the phenethyl moiety are relatively severe and can tend to disrupt the integrity of the core tetralin, chromane, or thiochromane molecule. It has been discovered that the cleavage can be carried out in a much more facile and efficient manner requiring only mild cleavage conditions when the particular α-phenethylamine which is used is p-nitro-α-phenethylamine.
- Cleavage of the p-nitro-α-phenethyl moiety is achieved by reduction of the p-nitro group followed by acid-catalyzed solvolysis of the resulting p-amino-α-phenethyl moiety. Reduction of the nitro group can be accomplished by a wide range of reducing agents including, for example, titanium trichloride, lithium aluminum hydride, or zinc/acetic acid, or by catalytic hydrogenation. Solvolytic cleavage takes place when the monohydrochloride (or other monobasic salt) of the reduction product is treated with water or an alcohol at room temperature or, in some instances, at elevated temperatures. A particularly convenient condition for removing the p-nitro-α-phenethyl moiety is hydrogenation of the amine monohydrochloride in methanol over a platinum catalyst.
- As indicated hereinabove, compounds highly useful as intermediates to the compounds of this invention are the corresponding 8-bromo compounds. It has been discovered that the 8-bromo compounds in their optically active form are not available using routine methodology whereas they can be prepared using the described method employing p-nitro-α-phenethylamine.
- The compounds employed as initial starting materials in the synthesis of the compounds of this invention are well known and readily synthesized by standard procedures commonly employed by those of ordinary skill in the art. Moreover, each of the sequences described in the foregoing for producing compounds of this invention involves recognized reactions commonly employed by those of ordinary skill in the art.
- The pharmaceutically acceptable acid addition salts of this invention are typically formed by reacting a 1,2,3,4-tetrahydronaphthalene, chromane, thiochromane sulfoxide, or thiochromane sulfone of this invention with an equimolar or excess amount of acid. The reactants are generally combined in a mutual solvent such as diethyl ether or benzene, and the salt normally precipitates out of solution within about one hour to 10 days, and can be isolated by filtration.
- The following Examples further illustrate the compounds of the present invention and methods for their synthesis. The Examples are not intended to be limiting to the scope of the invention in any respect and should not be so construed.
- n-Butyllithium (3.5 mmole, 3.0 ml, 1.2 M in hexane) was added to a solution of 8-bromo-2-di-n-propylamino-1,2,3,4-tetrahydronaphthalene (1.0 g, 3.2 mmol) in THF (10 ml) at -78°C. The reaction was stirred at -78°C for 45 min and then n-pentanal (0.41 ml, 3.9 mmole) was added. After stirring at -78°C for 5 min, the reaction was warmed to room temperature and poured into dilute HCl solution. The resulting solution was washed once with ether and the ether layer discarded. The aqueous layer was made basic with NH₄OH solution and extracted with methylenechloride. The extract was dried (Na₂SO₄) and concentrated to give 0.95 g of the crude product.
- Purification by silica gel flash chromatography using 1:1 ether:hexane with a trace of NH₄OH gave 0.68 g of product MS(FD) m/e = 317.
- Pyridinium chlorochromate (0.9 g, 4.0 mmol) and 4Å molecular sieves (30 g) were added to a solution of 2-di-n-propylamino-8-(1′-hydroxy-1-pentyl)-1,2,3,4-tetrahydronaphthalene (0.63 g = 2.0 mmole) in methylene chloride (50 ml). The reaction was stirred at room temperature for 1½ hr at which time the reaction was quenched by the addition of methanol (50 ml). Ether was added until the reaction became cloudy and this material was added to a shorted silica gel column and eluted with ether. The eluent was concentrated. Elution of the column was continued with 10% methanol in methylene chloride and the eluent concentrated to give a residue which was triturated with methanol and filtered through Celite. The filtrate was combined with the crude product from the ether elution and concentrated. Purification of this material on a flash silica gel column using 1:3 ether:hexane with a trace of NH₄OH provided 240 mg of the title compound. MS(FD): m/e = 315. The oxalate salt was formed and crystallized from ethylacetate/hexanes to give 165 mg of white crystals. m.p. 107-108.5°C.
Elemental Analysis: - Theory:
- C, 68.12; H, 8.70; N, 3.45
- Found:
- C, 67.85; H, 8.67; N, 3.41.
- 2-Di-n-propylamino-8-bromo-1,2,3,4-tetrahydronaphthalene (1.0 g.; 3.2 mmole) was dissolved in 10 ml. of THF, and the mixture was cooled to -78°C. after which 2.2 ml. of n-butyllithium (1.6 M. in hexane) was added. The reaction mixture was stirred at -78°C. for 40 minutes. Ethyl trifluoroacetate (0.42 ml;3.5 mmole) was added and the mixture allowed to warm to room temperature after which it was poured into water, the pH adjusted to 12, and the mixture extracted with methylene chloride. The extract was dried over sodium sulfate and evaporated to give 1.1 g. of a residue.
- The residue was purified on a silica gel column which was eluted using a 3:1 mixture of hexane and ether containing a trace of ammonium hydroxide. Fractions containing the impure product were combined to give 240 mg. of a mixture which was further purified by treatment on a silica gel column. The appropriate fractions from this second chromatographic purification were combined with the pure fractions from the first chromatographic purification to obtain 240 mg. of product. The product was converted to the hydrobromide salt and the salt recrystallized from a mixture of ethyl acetate and hexane to give 150 mg. of the title compound as a tan solid, m.p. 142-144°C.
Elemental Analysis: - Theory:
- C, 52.95; H, 6.17; N, 3.43;
- Found:
- C, 53.19; H, 6.08; N, 3.35.
- 2-Di-n-propylamino-8-bromo-1,2,3,4-tetrahydronaphthalene (8.5 g.; 27.4 mmole) was dissolved in 80 ml. of THF and cooled to -78°C. after which 25.7 ml. of n-butyllithium (1.6 M in hexane) were added. The mixture was stirred at -78°C. for one hour after which 2.4 ml. (32.9 mmole) of propionaldehyde were added. The mixture was warmed to room temperature and then poured into water, and extracted with methylene chloride. The extract was dried over sodium sulfate and evaporated to give 9.1 g of a yellow oil.
- The oil was placed on a silica gel column and was eluted with a mixture of 3% methanol in methylene chloride containing a trace of ammonium hydroxide. The appropriate fractions were combined to give 6.5 g. (82.0%) of 2-di-n-propylamino-8-(1′-hydroxypropyl)-1,2,3,4-tetrahydronaphthalene as a clear oil.
- The foregoing product was dissolved in 250 ml. of methylene chloride, and 17.0 g. (78.7 mmole) of pyridinium chlorochromate (PCC) were added along with 30 g 4A molecular sieves. The mixture was stirred for three hours at room temperature after which 250 ml. of ether and Celite were added. The mixture was poured onto a short silica gel column and eluted with ether. Methanol was added to dissolve the brown sludge which had precipitated upon addition of ether to the reaction. This material was added to the column and eluted with 10% methanol in methylene chloride. The eluent was concentrated to give a brown oil which was further purified by column chromatography employing 2:1 hexanes:ether and then pure ether as solvent. Fractions containing the product were combined and concentrated to give 4.7 g of the product. The oxalate salt of 2.5 g of this material was formed and recrystallized three times from ethanol/ether to give the product as a white solid. (1.5 g, m.p. 114.5-115°C).
Elemental Analysis: - Theory:
- C, 66.82; H, 8.29; N, 3.71;
- Found:
- C, 67.07; H, 8.20; N, 4.00.
- 2-Di-n-propylamino-8-bromo-1,2,3,4-tetrahydronaphthalene (5.0 g.; 16.1 mmole) was dissolved in 50 ml of THF, and the mixture was cooled to -78°C. after which 21.0 ml of n-butyllithium (0.92 M in hexane) were added. The mixture was stirred for 30 minutes, and 1.85 ml (21.0 mmole) of butyraldehyde were added. The mixture was allowed to warm to room temperature and was stirred overnight after which it was poured into water and extracted with methylene chloride. The extract was dried over sodium sulfate and evaporated to give 6.4 g of a residue. The residue was placed on a silica gel column and was eluted with a mixture of 2% methanol in methylene chloride containing a trace of ammonium hydroxide. The appropriate fractions were combined to give 4.8 g of 2-di-n-propylamino-8-(1′-hydroxybutyl)-1,2,3,4-tetrahydronaphthalene as a thick oil.
- The oil (4.0 g.; 13.2 mmole) was dissolved in 200 ml of methylene chloride and 4A molecular sieves (30 g) were added. The mixture was stirred, and 10.0 g (46.2 mmole) PCC were added. Stirring was continued for three hours at room temperature after which the mixture was poured onto a pad of silica gel and eluted sequentially with ether and 3% methanol in methylene chloride containing a trace of ammonium hydroxide to recover the product as a brown oil.
- The oil was placed on a silica gel column and was eluted with a mixture of 3% methanol and methylene chloride containing a trace of ammonium hydroxide. The appropriate fractions were combined to obtain an oil which, when dissolved in ether, caused a brown precipitate to form. The precipitate was removed by filtration, and the filtrate was evaporated to give 3.0 g. of a light brown oil as the free base of the title compound.
- One gram of the oil was converted to the hydrobromide salt and was recrystallized from a mixture of methanol and ethyl acetate to give 0.9 g of the title compound as tan crystals, m.p. 122-123°C. Following a second recrystallization, 750 mg were recovered, m.p. 125-126.5°C.
Elemental Analysis: - Theory:
- C, 62.82; H, 8.43; N, 3.66;
- Found:
- C, 63.09; H, 8.22; N, 3.66.
- 2-Di-n-propylamino-8-bromo-1,2,3,4-tetrahydronaphthalene (1.0 g; 3.2 mmole) was dissolved in 10 ml of THF and cooled to -78°C after which 3.5 ml (1.0 M in hexane) of n-butyllithium were added. To the resulting mixture after 30 minutes was added 0.41 ml (3.5 mmole) of methyl isobutyrate; the mixture was stirred at -10°C for 30 minutes and then was poured into 10% aqueous hydrochloric acid, washed with ether, and the pH raised to 10. The mixture then was extracted with methylene chloride, and the extract was dried over sodium sulfate and evaporated to give 0.72 g of a residue.
- The residue was placed on a silica gel column and was eluted sequentially with a 4:1 mixture of hexane and ether containing a trace of ammonium hydroxide and then a 3:1 mixture of hexane and ether containing a trace of ammonium hydroxide. The appropriate fractions were combined to give 190 mg of the free base of the title compound.
- The compound was converted to its hydrobromide salt and was recrystallized from ethyl acetate to give 80 mg of the title compound as tan crystals, m.p. 175-176.5°C.
Elemental Analysis: - Theory:
- C, 62.82; H, 8.43; N, 3.66;
- Found:
- C, 62.54; H, 8.53; N, 3.44.
- 2-Di-n-propylamino-8-bromo-1,2,3,4-tetrahydronaphthalene (1.0 g; 3.2 mmole) was dissolved in 10 ml of THF and cooled to -78°C after which 3.5 ml of n-butyllithium (1.0 M in hexane) were added. After 30 minutes, 0.53 ml (3.5 mmole) of ethyl isovalerate was added, and the mixture was warmed to -10°C and maintained for 30 minutes. The mixture then was poured into dilute acid, washed with ether, and the pH adjusted to 10. The mixture was extracted with methylene chloride, and the extract was dried over sodium sulfate and evaporated to give 0.83 g of a residue.
- The residue was placed on a silica gel column and was eluted sequentially a 4:1 mixture of hexane and ether containing a trace of ammonium hydroxide and then a 3:1 mixture of hexane and ether containing a trace of ammonium hydroxide. The appropriate fractions were combined to give 50 mg of the free base of the title compound.
- The free base was converted to the hydrobromide salt which was recrystallized from a mixture of ethyl acetate and hexane to give 30 mg of the title compound as a tan powder, m.p. 131-132°C.
Elemental Analysis: - Theory:
- C, 63.63; H, 8.64; N, 3.53;
- Found:
- C, 63.35; H, 8.42; N, 3.83.
- 2-Di-n-propylamino-8-bromo-1,2,3,4-tetrahydronaphthalene (1.0 g; 3.2 mmole) was dissolved in 20 ml of THF and cooled to -78°C after which 4.7 ml of n-butyllithium (0.82 M in hexane) was added. The mixture was stirred for 30 minutes at -78°C after which 0.56 ml (4.2 mmole) of methyl trimethyl acetate was added. The mixture was allowed to warm to room temperature and then was poured into water and extracted with methylene chloride. The extract was dried over sodium sulfate and evaporated to give 1.6 g of a residue.
- The residue was placed on a silica gel column and was eluted with a 3:1 mixture of hexane and ether containing a trace of ammonium hydroxide. The appropriate fractions were combined to give 140 mg of the free base of the title compound.
- The free base was converted to the hydrobromide salt and was recrystallized from methanol/ethyl acetate to give 80 mg of the title compound, m.p. 157-158°C.
Elemental Analysis: - Theory:
- C, 63.63; H, 8.65; N, 3.53;
- Found:
- C, 63.39; H, 8.46; N, 3.43.
- 2-Di-n-propylamino-8-bromo-1,2,3,4-tetrahydronaphthalene (1.0 g; 3.2 mmole) was dissolved in 10 ml of THF and cooled to -78°C after which 2.8 ml of n-butyllithium (1.27 M in hexane) were added. The mixture was stirred at -78°C for 45 minutes after which 0.59 ml (3.5 mmole) of ethyl cyclohexanecarboxylate was added. The mixture was warmed to room temperature and then was poured into a 10% hydrochloric acid solution, washed with ether, the pH adjusted to 10 with ammonium hydroxide, and extracted with methylene chloride. The extract was dried over sodium sulfate and evaporated to give 0.8 g of a residue.
- The residue was placed on a silica gel column and was eluted with a 3:1 mixture of hexane and ether containing a trace of ammonium hydroxide. The appropriate fractions were combined to give 0.36 g of the title compound.
- Butyllithium (1.2 M in hexane, 3.0 ml, 3.5 mmole) was added to a solution of 8-bromo-2-di-n-propylamino-1,2,3,4-tetrahydronaphthylene (1.0 g, 3.2 mmole) in THF (10 ml) at -78° and stirred for 45 minutes. Cyclohexanecarboxaldehyde (0.47 ml, 3.9 mmole) was added. The reaction was stirred at -78° for five minutes, warmed to room temperature, poured into dilute HCl solution and washed with ether. The aqueous layer was made basic with NH₄OH and extracted with methylene chloride. The extract was dried (Na₂SO₄) and concentrated to give 1.1 g of the crude product. The crude product was dissolved in methylene chloride (50 ml) and molecular sieves and pyridinium chlorochromate (1.4 g, 6.4 mmole) added. The reaction was stirred at room temperature for two hours. Methanol (50 ml) was added and the reaction concentrated to provide a slurry. The slurry was dissolved in methylene chloride (50 ml) and enough ether was added to give a cloudy solution. This material was added to a pad of silica gel and eluted with ether.
- The silica gel pad was eluted with 10% methanol in methylene chloride and the eluent concentrated to give an oily residue. This material was triturated with methanol and filtered through Celite. This filtrate was combined with the ether solution from above and concentrated. This material was dissolved in methylene chloride. Ether was added until the solution became cloudy and then filtered through florisil. The filtrate was concentrated to give 560 mg of an oil which was purified by silica gel flash chromatography using 3:1 hexane:ether containing a trace of NH₄OH as solvent. Appropriate fractions were combined and concentrated to give 350 mg of the desired compound. The oxalate salt was formed and crystallized from ethyl acetate/hexane to give 370 mg of a white solid. m.p. 98.5-100°.
Elemental Analysis: - Theory:
- C, 69.58; H, 8.64; N,3.25;
- Found:
- C, 69.28; H, 8.87; N, 3.00.
- 2-Di-n-propylamino-8-bromo-1,2,3,4-tetrahydronaphthalene (1.0 g; 3.2 mmole) was dissolved in 20 ml of THF and cooled to -78°C after which 3.0 ml of n-butyllithium (1.6 M in hexane) was added. The mixture was stirred at -78°C for one hour after which 0.5 ml (4.8 mmole) of benzaldehyde was added. Stirring was continued for 15 minutes, and the mixture was allowed to warm to room temperature and then was poured into water and extracted with methylene chloride. The extract was dried over sodium sulfate and evaporated to give 1.4 g of a yellow oil.
- The oil was placed on a silica gel column and was eluted with a 1:1 mixture of hexane and ether containing a trace of ammonium hydroxide. The appropriate fractions were combined to give 0.9 g of 2-di-n-propylamino-8-(α-hydroxybenzyl)-1,2,3,4-tetrahydronaphthalene.
- The foregoing product (0.83 g; 2.5 mmole) was dissolved in 50 ml of methylene chloride, and about 1 g of molecular sieves was added followed by 1.9 g (8.6 mmole) of PCC. The mixture was stirred for two hours after which it was diluted with ether and poured onto a silica gel column. The column was eluted with ether and then with a mixture of 10% methanol and methylene chloride. The fractions were combined, and the residue was dissolved in methanol and the solution was filtered through a pad of Celite. The filtrate was evaporated, and the residue was placed on a Florisil column which was eluted with a 2:1 mixture of hexane and ether. The appropriate fractions were combined to give 0.5 g of the free base of the title compound.
- The free base was converted to the tosylate salt which was recrystallized from a mixture of acetone and ether to give 125 mg of the title compound as a white powder, m.p. 148.5-149°C.
Elemental Analysis: - Theory:
- C, 70.97; H, 7.35; N, 2.76;
- Found:
- C, 71.18; H, 7.27; N, 2.74.
- 2-Di-n-propylamino-8-bromo-1,2,3,4-tetrahydronaphthalene (1.0 g; 3.2 mmole) was dissolved in 10 ml of THF and cooled to -78°C after which 3.5 ml of n-butyllithium (1.0 M in hexane) were added. The mixture was stirred for one hour at -78°C after which 680 mg (1.5 equivalents) of 4-chlorobenzaldehyde in THF were added. The mixture was stirred for 15 minutes at -78°C and then was allowed to warm to room temperature. The mixture was poured into a 10% aqueous hydrochloric acid solution, washed with ether, the pH adjusted to 10 with ammonium hydroxide, and extracted with methylene chloride. The extract was dried over sodium sulfate and evaporated to give 1.5 g of a residue.
- The residue was placed on a silica gel column and was eluted with a 1:1 mixture of hexane and ethyl acetate containing a trace of ammonium hydroxide. The appropriate fractions were combined to give 1.3 g of substantially pure 2-di-n-propylamino-8-(α-methyl-4′-chlorobenzyl)-1,2,3,4-tetrahydronaphthalene.
- The foregoing product (3.2 mmole) was dissolved in 50 ml of methylene chloride, and 30 g of 4A molecular sieves were added followed by 1.4 g (6.4 mmole) of PCC. The mixture was stirred for one hour and then was diluted with ether and poured through a pad of silica gel and the silica gel rinsed with ether. The filtrate was evaporated. The silica gel was washed with a mixture of 10% methanol and methylene chloride, and the latter filtrate was evaporated and the reside dissolved in methanol and filtered twice. This filtrate was combined with the ether filtrate, and the resultant mixture was placed on a silica gel column and eluted with a 2:1 mixture of hexane and ether containing a trace of ammonium hydroxide. The appropriate fractions were combined to give 0.3 g of the title compound.
- ms(FD): m/e = 369.
- 2-Di-n-propylamino-8-bromo-1,2,3,4-tetrahydronaphthalene (1.0 g; 3.22 mmole) dissolved in THF (25 ml) was cooled to -78°C, and 2.5 ml of n-butyllithium (1.27 M in hexane) were added. After one hour, o-fluorobenzoyl chloride (0.38 ml, 3.22 mmol) was added. The mixture was stirred for 10 minutes at -78°C after which the reaction was quenched by addition of water at -78°C. The reaction was poured into dilute HCl solution and extracted with methylene chloride. The aqueous layer was made basic with NaOH and extracted with methylene chloride. The basic extract was dried (Na₂SO₄) and concentrated to give 200 mg of residue which by nmr did not contain product. The extract from the acidic material was dried (Na₂SO₄) and concentrated to give 2.0 g of a residue. Purification of this material by flash silica gel chromatography using 1:1 ether:hexane containing a trace of ammonium hydroxide as solvent provided the free base of the title compound (340 mg). The salt of 130 mg of this material with p-toluene sulfonic acid was prepared and crystallized from ethyl acetate/ether to provide 118 mg of the title compound. m.p. 107-109°C.
Elemental Analysis: - Theory:
- C, 68.55; H, 6.90; N, 2.66;
- Found:
- C, 68.41; H, 7.02; N, 2.65.
- 2-Di-n-propylamino-8-bromo-1,2,3,4-tetrahydronaphthalene (5.0 g; 16.1 mmole) was dissolved in 25 ml of THF and cooled to -78°C after which 3.22 ml of n-butyllithium (1 M in hexane) was added. The mixture was maintained at -78°C for 1.5 hours. This solution was transferred via cannula to a solution of methyl methoxyacetate (7.5 ml, 160 mmol) in THF at -78°C. The reaction mixture was stirred at room temperature overnight, poured into NaHCO₃ solution and extracted with CH₂Cl₂. The extract was dried (Na₂SO₄) and concentrated to give 6.8 g of crude product.
- The material then was placed on a chromatographic column, and the product was eluted using 4% methanol in methylene chloride containing a trace of ammonium hydroxide. The appropriate fractions were combined to give 1.4 g of the title compound.
- The oxalic acid salt was formed and three times recrystallized from ethyl acetate to give the salt as a white powder, m.p. 118°C.
- Butyllithium (1.2M in hexane; 2.8 ml; 3.4 mmol) was added to a solution of 8-bromo-2-di-n-propylamino-1,2,3,4-tetrahydronaphthalene (1 g; 3.22 mmol) in THF (50 ml) at -78°C. After 1.5 hr., a solution of trimethyltin chloride (1.3 g, 2.0 mmol) in THF (20 ml) was added. The reaction mixture was allowed to warm to room temperature, stirred overnight at room temperature, poured into water, and extracted with methylene chloride. The extract was dried (Na₂SO₄) and concentrated to give the crude product. Purification by chromatography using 1:10 methanol:methylene chloride gave 1.2 g of the desired product which was used directly in the next step.
- Bis-triphenylphosphine palladium dichloride (120 mg) was added to a solution of 2-dipropylamino-8-trimethylstannyl-1,2,3,4-tetrahydronaphthalene (500 mg, 1.27 mmol) in benzene (20 ml). Methoxyacetyl chloride (1.5 ml; 1.77 g; 16.5 mmol) was added. The reaction mixture was stirred at room temperature overnight and then heated to reflux for 5 hr. The reaction mixture was poured into water and extracted with methylene chloride. The extract was dried (MgSO₄) and concentrated to give 800 mg of crude product. Purification by chromatography using 1:10 methanol: methylene chloride as solvent gave 380 mg of 2-di-n-propylamino-8-methoxyacetyl-1,2,3,4-tetrahydronaphthalene.
- A solution of n-butyllithium (1.6 M in hexane, 15.1 ml, 24.2 mmole) was added to a solution of 8-bromo-2-di-n-propylamino-1,2,3,4-tetrahydronaphthalene (5.0 g, 16.1 mmole) in THF (50 ml) at -78° and the reaction stirred at -78° for one hour. Gaseous carbon dioxide was bubbled through the reaction at -78° until the deep violet color which forms dissipates. Methyllithium (1.4 M in ether, 23 ml) was added. The reaction was stirred at -78° for 30 minutes and warmed to room temperature. The reaction was stirred for an additional ten minutes at room temperature at which time the pink color had been lost. An additional 10 ml of the methyllithium solution was added and the reaction became pink once again. After 15 minutes, the pink color was lost and an additional 10 ml of the methyllithium solution added. The reaction was poured onto ice, made acidic with hydrochloric acid and extracted with ether. The aqueous layer was made basic and extracted with methylenechloride. The basic extracts were dried (Na₂SO₄) and concentrated to give 3.8 g of crude product. Purification by flash silica gel chromatography using 2:1 hexane:ether containing trace ammonium hydroxide provided the free base of the title compound as a yellow oil (2.7 g, 61%).
- The maleate salt was prepared and crystallized from methanol/ethyl acetate/hexane to give the maleate salt. m.p. 115-116°.
Elemental Analysis: - Theory:
- C, 67.84; H, 8.04; N, 3.60;
- Found:
- C, 68.07; H, 8.02; N, 3.55.
- Alternatively, the hydrochloride salt can be prepared. Crystallization from ethanol/ether provided the hydrochloride salt as colorless crystals. m.p. 124-125°C.
Elemental Analysis: - Theory:
- C, 69.77; H, 9.11; N, 4.52;
- Found:
- C, 69.91; H, 9.20; N, 4.53.
- n-Butyllithium (1.6 M in hexane, 60.5 ml, 96.8 mmole) was added to a solution of 8-bromo-2-di-n-propylamino-1,2,3,4-tetrahydronaphthalene (20.0 g, 64.5 mmole) in THF (200 ml) at -78° and the reaction stirred at -78° for one hour. Acetaldehyde (4.3 ml, 77.4 mmole) was added and the reaction allowed to warm to room temperature. The reaction was poured into water, made basic with ammonium hydroxide and extracted with methylene chloride. The extract was dried (Na₂SO₄) and concentrated to give 21.4 g of a yellow oil.
- To a solution of this yellow oil in methylene chloride (800 ml) was added 4Å molecular sieves (30 g) and pyridinium chlorochromate (27.8 g, 129 mmole). The reaction was stirred at room temperature for 1½ hours. Methanol was added and the reaction filtered through a pad of Celite. The filtrate was concentrated and purified by chromatography over Florisil using 2:1 hexane:ether as solvent. The appropriate fractions were combined to give 6.8 g of the desired product. The solids from the filtration through Celite were suspended in 10% Methanol in methylene chloride and purified by Florisil column chromatography using 10% methanol in methylenechloride as solvent. The fractions containing product were combined and concentrated to give a residue which was taken up in a small volume of methylene chloride. Ether was added to this solution until the material became slightly cloudy. The solution was added to a pad of silica gel and eluted with ether. This material was combined with the product from the original filtrate and concentrated to give the methylketone as a light brown oil. (9.9 g).
- As noted above, the compounds (Formula I) of this invention, especially those in which A is
have binding affinity for the 5-HT1A receptor. Therefore, another embodiment of the present invention is a method of effecting agonist action at the 5-HT1A receptors which comprises administering to a mammal in need thereof a pharmaceutically effective amount of a compound of the invention. - The term "pharmaceutically effective amount", as used herein, represents an amount of a compound of the invention which is capable of binding to serotonin 1A receptors. The specific dose of compound administered according to this invention will, of course, be determined by the particular circumstances surrounding the case, including, for example, the compound administered, the route of administration, and the condition being treated. A typical daily dose generally will contain from about 0.01 mg/kg to about 20 mg/kg of the active compound of this invention. Preferred daily doses generally will be from about 0.05 to about 10 mg/kg, and ideally from about 0.1 to about 5 mg/kg.
- The compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. A special feature of the compounds of this invention is that they are extremely selective in effecting agonist action at serotonin 1A receptors relative to other serotonin receptors.
- A variety of physiologic functions have been shown to be subject to influence by brain serotonergic neural systems. As such, the compounds of this invention are believed to have the ability to treat in mammals a variety of 5-HT mediated states and disorders such as sexual disorders, eating disorders, depression, alcoholism, pain, senile dementia, anxiety, and smoking. Therefore, the present invention also provides methods of treating the above disorders at rates set forth above for agonist action in mammals at 5-HT receptors.
- The following experiment was conducted to demonstrate the ability of the compounds of the present invention to effect agonist action at the serotonin 1A receptors. This general procedure is set forth in Wong et al., J. Neural Transm. 71:207-218 (1988).
- Male Sprague-Dawley rats (110-150 g) from Harlan Industries (Cumberland, IN) were fed a Purina Chow ad libitum for at least 3 days before being used in the studies. Rats were killed by decapitation. The brains were rapidly removed, and the cerebral cortices were dissected out at 4°C.
- Brain tissues were homogenized in 0.32 M sucrose. After centrifugation at 1000 x g for 10 min and then at 17000 x g for 20 min, a crude synaptosomal fraction was sedimented. The pellet was suspended in 100 vol of 50 mM Tris-HCl, pH 7.4, incubated at 37°C for 10 min, and centrifuged at 50000 x g for 10 min. The process was repeated and the final pellet was suspended in ice-chilled 50 mM Tris-HCl, pH 7.4. By the radioligand binding method, sites specifically labeled by tritiated 8-hydroxy-2-dipropylamino-1,2,3,4-tetrahydronaphthalene (³H-8-OH-DPAT) have been identified as 5-HT1A receptors.
- Binding of (³H-8-OH-DPAT) was performed according to the previously described method [Wong et al., J. Neural Transm. 64:251-269 (1985)]. Briefly, synaptosomal membranes isolated from cerebral cortex were incubated at 37°C for 10 min. in 2 ml of 50 mM Tris-HCl, pH 7.4; 10 µM pargyline; 0.6 mM ascorbic acid; 0.4 nM ³H-8-OH-DPAT; and from 1 to 1000 nM of test compound. Binding was terminated by filtering samples under reduced pressure through glass fiber (GFB) filters. The filters were washed twice with 5 ml of ice cold buffer and placed in scintillation vials with 10 ml of PCS (Amersham/Searle) scintillation fluid. Radioactivity was measured with a liquid scintillation spectrometer. Unlabeled 8-OH-DPAT at 10 µM was also included in separate samples to establish non-specific binding. Specific binding of ³H-8-OH-DPAT is defined as the difference of radioactivity bound in the absence and in the presence of 10 µM unlabeled 8-OH-DPAT.
- The results of the evaluation of various compounds of the present invention are set forth below in Table I. In Table I, the first column provides the Example Number of the compound evaluated; the next 7 columns identify the structure of the compound evaluated when taken with the formula set forth in the heading; the next-succeeding column identifies the salt form of the compound evaluated; and the final column provides the amount of the test compound expressed in nanomolar concentration required to inhibit the binding of ³H-8-OH-DPAT) by 50%, and is indicated in Table I as IC₅₀.
- The compounds of this invention are preferably formulated prior to administration. Therefore, another embodiment of the present invention is a pharmaceutical formulation comprising a compound of the invention and a pharmaceutically acceptable carrier, diluent or excipient therefor.
- The present pharmaceutical formulations are prepared by known procedures using well known and readily available ingredients. In making the compositions of the present invention, the active ingredient will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, paper or other container. When the carrier serves as a diluent, it may be a solid, semisolid or liquid material which acts as a vehicle, excipient or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, sterile packaged powders, and the like.
- Examples of suitable carriers, excipients, and diluents are lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water syrup, methyl cellulose, methyl-hydroxybenzoates, propyl hydroxybenzoates, talc, magnesium stearate, and mineral oil. The formulations may additionally include lubricating agents, wetting agents, emulsifying agents, suspending agents, preserving agents, sweetening agents, flavoring agents, and the like. The compositions of the invention may be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.
- The compositions are preferably formulated in a unit dosage form, each dosage generally containing from about 0.1 to about 500 mg, and preferably from about 1 to about 250 mg, of the active ingredient. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier.
- The following formulation examples are illustrative only and are not intended to limit the scope of the invention in any way.
-
- The above ingredients are mixed and filled into hard gelatin capsules in 460 mg quantities.
-
-
- The active compound is mixed with ethanol and the mixture added to a portion of the propellant 22, cooled to -30°C. and transferred to a filling device. The required amount is then fed to a stainless steel container and diluted with the remainder of the propellant. The valve units are then fitted to the container.
-
- The active ingredient, starch and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly. The aqueous solution containing polyvinylpyrrolidone is mixed with the resultant powder, and the mixture then is passed through a No. 14 mesh U.S. sieve. The granules so produced are dried at 50°C and passed through a No. 18 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate and talc, previously passed through a No. 60 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg.
-
- The active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No. 45 mesh U.S. sieve, and filled into hard gelatin capsules in 200 mg quantities.
-
- The active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2 g capacity and allowed to cool.
-
- The active ingredient is passed through a No. 45 mesh U.S. sieve and mixed with the sodium carboxymethyl cellulose and syrup to form a smooth paste. The benzoic acid solution, flavor and color are diluted with a portion of the water and added, with stirring. Sufficient water is then added to produce the required volume.
-
- The solution of the above ingredients generally is administered intravenously at a rate of 1 ml per minute to a subject suffering from depression.
Claims (13)
- A compound of the formula
R₃ is hydrogen; or
R and R₃ taken together are a divalent group of the formula -CH₂CH₂CH₂-;
R₁ is hydrogen, C₁-C₄ alkyl, C₃-C₄ alkenyl, cyclopropylmethyl, aryl (C₁-C₄-alkyl ), -COR₄, -(CH₂)nS(C₁-C₄ alkyl ) or -(CH₂)nCONR₅R₆;
n is an integer from 1 to 4;
R₄ is hydrogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, or phenyl;
R₅ and R₆ are independently hydrogen, C₁-C₄ alkyl, or C₃-C₇ cycloalkyl with the proviso that when one of R₅ or R₆ is cycloalkyl the other is hydrogen;
X is -CH₂-, -O-, -S-,
and pharmaceutically acceptable acid addition salts thereof. - A compound as claimed in claim 1 or 2, in which R and R₃ taken together are a divalent group of the formula -CH₂CH₂CH₂-.
- A compound as claimed in any of claims 1 to 3, in which X is -CH₂-.
- A compound as claimed in any of claims 1 to 4, in which R₂ is C₁-C₈ alkyl.
- A compound as claimed in Claim 5, in which R₂ is C₁-C₅ alkyl.
- A compound as claimed in any of claims 1 to 6, in which R and R₁ are both C₁-C₄ alkyl.
- A compound as claimed in claim 7, in which R and R₁ are both n-propyl.
- A compound as claimed in any of claims 1 to 8, in which R₂ is t-butyl.
- A compound as claimed in any of claims 1 to 8, in which R₂ is isopropyl.
- A process for preparing a compound of the formula
R₃ is hydrogen; or
R and R₃ taken together are a divalent group of the formula -CH₂CH₂CH₂-;
R₁ is hydrogen, C₁-C₄ alkyl, C₃-C₄ alkenyl, cyclopropylmethyl, aryl(C₁-C₄-alkyl), -COR₄, -(CH₂)nS(C₁-C₄ alkyl ) or -(CH₂)nCONR₅R₆;
n is an integer from 1 to 4;
R₄ is hydrogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, or phenyl;
R₅ and R₆ are independently hydrogen, C₁-C₄ alkyl, or C₃-C₇ cycloalkyl with the proviso that when one of R₅ or R₆ is cycloalkyl the other is hydrogen;
X is -CH₂-, -O-, -S-,
which comprises reacting a compound of the formulaA) with a compound of the formula R₂COZ in which R₂ is as herein defined and Z is halo, alkoxy, hydroxy, aryloxy, -S-(C₁-C₃ alkyl), -OCO₂R′,B) with a compound of the formula R₂C(O)H in which R₂ is as herein defined in the presence of n-butyllithium followed by oxidation of the resulting product.
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US (5) | US5286753A (en) |
EP (1) | EP0471515B1 (en) |
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DK (1) | DK0471515T3 (en) |
ES (1) | ES2100211T3 (en) |
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US5385930A (en) * | 1992-05-18 | 1995-01-31 | Adir Et Compagnie | Thiochroman compounds |
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ATE121740T1 (en) * | 1989-03-22 | 1995-05-15 | Ciba Geigy Ag | NEW BENZOTHIOPYRANYLAMINES. |
US5616610A (en) * | 1989-12-22 | 1997-04-01 | Astra Aktiebolag | (R)-5-carbamoyl-8-fluoro-3-N,N-disubstituted-amino-3,4-dihydro-2H-1-benzopyrans |
US5420151A (en) * | 1989-12-22 | 1995-05-30 | Aktiebolaget Astra | Chroman derivatives |
US5340838A (en) * | 1990-05-04 | 1994-08-23 | Eli Lilly And Company | Method of inhibiting gastric acid secretion with 2-phenylcyclopropylamines |
DK0471515T3 (en) * | 1990-08-15 | 1997-07-21 | Lilly Co Eli | Ring-substituted 2-amino-1,2,3,4-tetrahydronephthalenes, 3-aminochromanes and 3-aminothiochromanes |
DE69218813T2 (en) * | 1991-02-08 | 1997-08-14 | Lilly Co Eli | Ring-substituted 2-amino-1,2,3,4-tetrahydronaphthalenes |
AU654573B2 (en) * | 1991-08-21 | 1994-11-10 | Eli Lilly And Company | Benzo(f)quinolinones |
WO1994022495A1 (en) * | 1993-03-31 | 1994-10-13 | The Trustees Of The University Of Pennsylvania | Dopamine d-3 and serotonin (5-ht1a) receptor ligands and imaging agents |
US5837702A (en) * | 1993-10-07 | 1998-11-17 | Bristol-Myers Squibb Co. | 4-arylamino-benzopyran and related compounds |
FR2717175B1 (en) * | 1994-03-11 | 1996-06-14 | Adir | New alkylaminoindane compounds, processes for their preparation and pharmaceutical compositions containing them. |
US5482942A (en) * | 1994-06-28 | 1996-01-09 | American Home Products Corporation | (3,4-dioxocyclobuten-1-yl)chromene, indene, and dihydronaphthalenone derivatives as smooth muscle relaxants |
US5612370A (en) * | 1995-06-07 | 1997-03-18 | Bristol-Myers Squibb Company | Phenylglycine and phenylalaninen amido benzopyran derivatives |
US5869478A (en) * | 1995-06-07 | 1999-02-09 | Bristol-Myers Squibb Company | Sulfonamido substituted benzopyran derivatives |
US5612323A (en) * | 1995-06-07 | 1997-03-18 | Bristol-Myers Squibb Company | Phosphinic ester substituted benzopyran derivatives |
US5629429A (en) * | 1995-06-07 | 1997-05-13 | Bristol-Myers Squibb Company | Process for preparing 4-arylamino-benzopyran and related compounds |
EP1052982A4 (en) * | 1997-04-30 | 2004-10-06 | Lilly Co Eli | AMINOTETRALINS AS 5-HT 1D$g(a)? AGONISTS |
US6355674B1 (en) | 1997-04-30 | 2002-03-12 | Eli Lilly And Company | Aminotetralins as 5-HT1D α Agonists |
US5962488A (en) | 1998-04-08 | 1999-10-05 | Roberts Laboratories, Inc. | Stable pharmaceutical formulations for treating internal bowel syndrome containing isoxazole derivatives |
FR2792529B1 (en) * | 1999-04-26 | 2001-09-28 | Sod Conseils Rech Applic | NOVEL PHARMACEUTICAL COMPOSITIONS COMPRISING 2-ISOXAZOLE-8-AMINOTETRALINE DERIVATIVES |
US7060847B2 (en) * | 2003-07-18 | 2006-06-13 | Roche Diagnostics Operations, Inc. | Ecstasy-class derivatives, immunogens, and antibodies and their use in detecting ecstasy-class drugs |
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- 1991-08-13 IL IL99175A patent/IL99175A/en not_active IP Right Cessation
- 1991-08-13 AU AU82403/91A patent/AU652569B2/en not_active Ceased
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- 1991-08-13 FI FI913833A patent/FI913833A/en not_active Application Discontinuation
- 1991-08-14 JP JP3204223A patent/JPH04244050A/en active Pending
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- 1991-08-14 YU YU140291A patent/YU48695B/en unknown
- 1991-08-14 NO NO913175A patent/NO176094C/en not_active IP Right Cessation
- 1991-08-14 ZA ZA916425A patent/ZA916425B/en unknown
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- 1991-08-14 MY MYPI91001472A patent/MY110619A/en unknown
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1993
- 1993-04-16 US US08/048,553 patent/US5286753A/en not_active Expired - Fee Related
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1995
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